close

Вход

Забыли?

вход по аккаунту

?

Disorders of leftЦright asymmetry Heterotaxy and situs inversus.

код для вставкиСкачать
American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 151C:307 – 317 (2009)
A R T I C L E
Disorders of Left–Right Asymmetry:
Heterotaxy and Situs Inversus
MARDI J. SUTHERLAND AND STEPHANIE M. WARE*
Cilia function is critical to the development of proper organ laterality. Primary ciliary dyskinesia (PCD) causes
randomization of situs. Heterotaxy, or situs ambiguus, is an abnormal arrangement of the thoracic and abdominal
organs that results in congenital anomalies. Animal models and developmental biological approaches have
defined pathways required during embryogenesis for proper left–right pattern formation. New candidates for
genetic causes of human laterality disorders have emerged from recent studies on the assembly, transport, and
signaling functions of cilia at the node as well as identification of cilia within the developing heart. There is
evidence that deleterious genetic variants within one or more developmental pathways may disrupt signaling in a
synergistic or combinatorial fashion to cause congenital anomalies. The molecular pathways underlying PCD and
heterotaxy are being discovered at a rapid pace, and there is increasing recognition of the overlap between these
two categories of laterality disorders and their relationship to isolated cardiovascular malformations. This review
focuses on the clinical manifestations, molecular mechanisms, and human genetics of these disorders of
laterality. ß 2009 Wiley-Liss, Inc.
KEY WORDS: cilia; heterotaxy; left–right asymmetry; situs inversus; primary ciliary dyskinesia
How to cite this article: Sutherland MJ, Ware SM. 2009. Disorders of left–right asymmetry:
Heterotaxy and situs inversus. Am J Med Genet Part C Semin Med Genet 151C:307–317.
INTRODUCTION
Heterotaxy and situs inversus are disorders of laterality in which the internal
organs do not have their typical pattern
of asymmetry. In situs inversus, the
internal organ arrangement is mirror
image of normal anatomy, termed situs
solitus. Baillie first described situs inversus in 1793. One hundred forty years
later, Kartagener [1933], a pulmonoloStephanie M. Ware, M.D., Ph.D. is an
Assistant Professor in the Divisions of
Molecular Cardiovascular Biology, Human
Genetics, and Cardiology at Cincinnati Children’s Hospital Medical Center. Her laboratory
investigates the genetic basis of cardiac
disease in children. She is board certified in
Pediatrics and Clinical Genetics.
Mardi J. Sutherland is a graduate student
in the Molecular and Developmental Biology
graduate program at Cincinnati Children’s
Hospital Medical Center and the University
of Cincinnati College of Medicine.
*Correspondence to: Stephanie M. Ware,
M.D., Ph.D., Cincinnati Children’s Hospital
Medical Center, 240 Albert Sabin Way, MLC
7020, Cincinnati, OH 45229.
E-mail: stephanie.ware@cchmc.org
DOI 10.1002/ajmg.c.30228
Published online 27 October 2009 in Wiley
InterScience
(www.interscience.wiley.com)
ß 2009 Wiley-Liss, Inc.
gist, reported four patients with the triad
of sinusitis, bronchiectasis, and situs
inversus. In the 1970s, the relationship
between situs inversus and ciliary
abnormalities was established when
Afzelius reported cilia immotility in
infertile males, half of whom had
Kartagener’s triad [Afzelius, 1976]. His
In the 1970s, the relationship
between situs inversus and
ciliary abnormalities was
established when Afzelius
reported cilia immotility in
infertile males, half of
whom had Kartagener’s triad.
His speculation that cilia
played a role in determining
laterality would require
several more decades
to prove.
speculation that cilia played a role
in determining laterality would require
several more decades to prove.
Primary ciliary dyskinesia (PCD),
previously known as immotile cilia
syndrome, is one of the most widely
recognized ciliopathies. Kartagener
syndrome (OMIM #244400), in which
situs is randomized, is a subset of PCD
and accounts for approximately 20%
of these cases. PCD has an estimated
prevalence of 1:15,000.
Heterotaxy, or situs ambiguus, is an
abnormal arrangement of the thoracic
and/or abdominal viscera. It is characterized by multiple congenital malformations, with the major morbidity
and mortality resulting from complex
cardiovascular malformations. A variety
of descriptive (e.g., asplenia or
polysplenia syndrome, left or right
isomerism) or eponymous (e.g., Ivemark
syndrome) designations arose in an
attempt to precisely classify constellations of clinical and phenotypic features
of patients with laterality disorders.
In reality, both clinical observation
and molecular investigation indicate
that exceptions are the rule, and the
308
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
designations encompass an overlapping
spectrum. It is therefore more precise
and clinically useful to use the term
heterotaxy or situs ambiguus followed
by the exact anatomic description.
The International Nomenclature Committee for Pediatric and Congenital
Heart Disease recently published cardiac
evaluation and nomenclature recommendations for heterotaxy, and details
of the cardiac and extra-cardiac anomalies have been reviewed in detail
previously [Zhu et al., 2006; Jacobs
et al., 2007; Ware and Belmont, 2008].
Heterotaxy accounts for approximately 3% of all congenital heart defects.
‘‘Classic’’ heterotaxy, in which typical
cardiac defects are seen in conjunction
with visceral situs anomalies, has an
The International
Nomenclature Committee for
Pediatric and Congenital Heart
Disease recently published
cardiac evaluation and
nomenclature recommendations
for heterotaxy.
estimated prevalence of 1:10,000 [Lin
et al., 2000]. Because of the wide
phenotypic spectrum identified in laterality disorders, it is likely that this underestimates the true prevalence. It is now
clear, for example, that gene mutations
that cause classic forms of heterotaxy
can also result in isolated cardiovascular
malformations without evidence of visceral anomalies [Megarbane et al., 2000;
Goldmuntz et al., 2002; Ware et al., 2004].
Similarly, patients with PCD can have
cardiovascular malformations with or
without dextrocardia. A recent study by
Kennedy et al. [2007] demonstrates that
6.3% of patients with PCD have heterotaxy. These data illustrate the spectrum
of disease caused by abnormal left–
right development during embryogenesis.
DIAGNOSIS AND
CLINICAL MANAGEMENT
Patients with PCD frequently have
neonatal respiratory distress, but the
diagnosis of a ciliopathy may not
be made until months or years later.
Classically, patients with PCD have
significant problems with mucociliary
clearance, leading to sinusitis, persistent
otitis media, or bronchiectasis (Table I).
Situs inversus or heterotaxy may occur.
ARTICLE
Infertility is reported in greater than 50%
of PCD males due to decreased or absent
sperm motility. Cystic fibrosis shares
many overlapping features and needs to
be ruled out. The standard for diagnosis
is transmission electron microscopy for
analysis of ciliary ultrastructure. Common findings include abnormalities of
the outer or inner dynein arms (most
frequent), radial spokes, central microtubules, or absence of cilia. Although
abnormal electron microscopy confirms
the diagnosis of PCD, normal electron
microscopy does not rule out the
diagnosis. Additional methods are being
developed to better analyze cilia structure and function, including analysis of
ciliary motility on high-speed videomicroscopy, analysis of mucociliary
clearance, demonstration of decreased
nasal nitric oxide levels, or immunohistochemical analysis of the outer dynein
arms [Zariwala et al., 2007]. Strict
clinical diagnostic criteria have not yet
been developed for PCD [Leigh et al.,
2009]. As more data regarding the
overlap of clinical features between
heterotaxy and PCD emerge, diagnostic
recommendations can be formalized
(Table I).
Heterotaxy is most frequently diagnosed in the newborn period due
TABLE I. Clinical Features and Diagnosis of PCD and Heterotaxy
PCD
Clinical features
Variable age of presentation
Neonatal respiratory distress
Situs inversus or heterotaxy
Chronic sinusits, otitis media, or bronchiectasis
Persistent cough, nasal congestion, or respiratory infection
Male infertility/impaired sperm motility
Diagnostic evaluation
Pedigree
Ultrastructural analysis (TEM) of cilia
Consider chromosomes and chromosome microarray analysis
Gene mutation analysis (DNAH5, DNAI1)
Imaging studies as necessary
TEM, transmission electron microscopy.
Heterotaxy
Presentation in infancy in classic form
Congenital heart disease, dextrocardia, or mesocardia
Malrotation, microgastria, abdominal situs anomalies
Biliary atresia
Vertebral or rib anomalies
Asplenia or polysplenia
Pedigree
Imaging studies to define anatomy (echocardiogram/cardiac MRI;
head ultrasound or brain MRI; upper gastrointestinal series;
abdominal ultrasound; chest X-ray and spine films; consideration
of hepatobiliary scintigraphy)
Chromosomes and chromosome microarray analysis
Consider gene mutation analysis (ZIC3)
ARTICLE
to cyanotic congenital heart disease.
These patients require an extensive
diagnostic evaluation and multiple
imaging studies in order to define their
anatomy (Table I). While it may not be
practical to perform all of the diagnostic
evaluations in a critically ill infant, the
spectrum of potential anomalies needs to
be recognized, particularly in the case of
sudden decompensation. All patients
should have chromosomes and chromosome microarray analysis due to associations with chromosome abnormalities,
as described in more detail below.
Strong consideration should be given
to ZIC3 mutation testing particularly
in males. The prevalence of PCD in
patients with heterotaxy remains to
be determined. Nevertheless, consideration should be given to evaluation for
PCD since respiratory and pulmonary
management could be optimized in
an attempt to improve the higher
than expected surgical morbidity and
mortality in this patient group. The
development of improved methods for
PCD diagnosis, as described above, is
important to better define the patient
subsets and direct management and
therapy.
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
(LPM), (5) signaling from the LPM to
organ primordia. Heterotaxy may result
from defects in any of these five steps.
Isolated dextrocardia or congenital heart
defects related to abnormal laterality can
also result from abnormalities at various
stages of left–right patterning. In contrast, situs inversus caused by PCD
usually results from defects in signaling
at the node involving cilia structure and
function.
Signaling Upstream of the Node
The early stage of left–right patterning
occurs before cilia are established at the
node, a transient embryonic organizer.
309
This involves processes including planar
cell polarity in which asymmetric
gradients are established within a cell,
across a sheet of cells and ultimately
throughout the embryo [Aw and Levin,
2009]. The signaling pathways and
molecular mechanisms underlying these
events during left–right patterning are
not yet well defined, and these early
steps of asymmetry may vary by model
organism. There is some evidence
that asymmetry is first established as
intracellular gradients [Palmer, 2004;
Vandenberg, 2009]. No pathogenic
mutations have been described at this
early stage of axis formation in humans
with laterality defects.
ETIOLOGY AND
MOLECULAR MECHANISMS
The left–right axis is established early
in development subsequent to the
development of anterior–posterior and
dorsal–ventral axes. A basic understanding of the embryonic tissues and molecular events necessary for left–right axis
formation is beneficial for initiating a
diagnostic work-up, understanding the
genetic basis of disease, and assessing
recurrence risk.
Recent work with model organisms
has offered a detailed view of the steps
taken to establish asymmetry in the
vertebrate. Figure 1 illustrates five steps
for left–right patterning: (1) signaling
upstream of the node, (2) signaling at the
node involving cilia structure and function, (3) leftward flow breaking bilateral
symmetry at the node, (4) transfer of
asymmetric gene expression from the
node to the lateral plate mesoderm
Figure 1. Overview of left–right asymmetry in the mouse embryo. Before the
establishment of the node or cilia, there is evidence for early intracellular asymmetry
involving mechanisms such as planar cell polarity (PCP). PCP also plays a later role in the
proper orientation of cilia at the node. In the second stage, the node and functioning
motile and sensory cilia form. Although the genetic control of node morphogenesis is
largely unknown, Notch signaling is necessary for both proper node structure as well as
later asymmetric nodal expression. Foxj1 is a master regulator of ciliogenesis, and
intraflagellar transport is required for cilia assembly. Centrally located monocilia are
motile and peripheral monocilia lack left–right dynein and are immotile. In stage 3, the
movement of cilia at the node creates a leftward flow of morphogens. FGF signaling
triggers the release of Shh and retinoic acid. An increase in cytoplasmic calcium occurs.
Nodal expression is initially bilateral, but becomes asymmetrically expressed on the left,
providing molecular evidence of left–right asymmetry. In stage 4, Nodal signal is
propagated from the node to the LPM where asymmetric gene expression is
established. The Nodal signal transduction pathway occurs when the TGF-b ligand
Nodal is cleaved to its active form. It requires EGF-CFC co-receptors to bind to Type I/II
activin receptors. Lefty proteins interfere with binding of the mature ligand. After
binding, phosphorylated Smad complexes translocate to the nucleus where they bind
DNA with co-factors such as FoxHI. Through this pathway, Nodal can activate Lefty1,
Lefty2, Pitx2 and its own expression in the LPM. In stage 5, asymmetric signaling is
propagated from the LPM to organ primordia in order for proper morphogenesis to
occur. IFT, intraflagellar transport; LPM, lateral plate mesoderm; PCP, planar cell
polarity.
310
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
Signaling at the Node Involving
Cilia Structure and Function
Although the existence of an organizing
left-right coordinator has been documented in all vertebrate species studied
to date, its structure varies. In mouse, this
structure is known as the ventral node; in
chick, Henson’s node; in zebrafish,
kupffer’s vesicle (KV); in Xenopus, the
gastrocoel roof plate (GRP); and in
rabbit, the posterior notochordal
plate (PNC) [Essner et al., 2002; Okada
et al., 2005; Lee and Anderson, 2008].
Although the existence of
an organizing left-right
coordinator has been
documented in all vertebrate
species studied to date, its
structure varies. In mouse, this
structure is known as the ventral
node; in chick, Henson’s node;
in zebrafish, kupffer’s vesicle
(KV); in Xenopus, the
gastrocoel roof plate (GRP);
and in rabbit, the posterior
notochordal plate (PNC).
Additionally, the coordinating structure
has recently been examined in pig. The
organizer is required for proper axis
formation prior to organogenesis. In
mouse, the node is present between
7.5 and 8.5 days post coitum, which is
equivalent to Carnegie stages 7–10 in
humans.
The node structure in pig and chick
begins with bilateral symmetry, but later
in development exhibits leftward displacement and asymmetric gene expression. These structural and molecular
changes result from cell migration to
the left of the node [Gros et al., 2009]. In
mouse, rabbit, and zebrafish, the organizing structures contain monociliated
cells with motile cilia which generate a
‘‘nodal flow.’’ Experimental evidence in
mouse and zebrafish has linked the
Notch pathway with both node formation and downstream activation of
asymmetric Nodal gene expression at
the node [Krebs et al., 2003; Przemeck
et al., 2003; Takeuchi et al., 2007].
Leftward fluid flow at the node results
from the clockwise rotational motion of
the cilia creating a unidirectional flow. In
many vertebrate species examined,
including rabbit, fish, and mouse, cilia
are detected as being tilted toward the
posterior axis [Nonaka et al., 2002;
Okada et al., 2005]. This posterior tilt
is predicted as a necessary component of
the leftward unidirectional flow at the
node, which is essential for proper left–
right asymmetry [Nonaka et al., 1998;
Okada et al., 1999].
There are two populations of cilia
located at the mouse node [McGrath
et al., 2003]. These consist of the
There are two populations of
cilia located at the mouse node.
These consist of the central
motile cilia and the peripheral
sensory cilia.
central motile cilia and the peripheral
sensory cilia. Typical motile cilia contain
nine microtubule doublets surrounding
two central microtubules and are
referred to as 9 þ 2 motile cilia. Motile
cilia of the node lack the two central
microtubules and are referred to as 9 þ 0
motile cilia. Sensory cilia (9 þ 0) also
lack the central microtubules but, in
addition, lack dynein arms and are
immotile. Proteins necessary for ciliary
movement are specific to motile cilia,
and include dynein proteins which make
up the inner and outer dynein arms
along the microtubules [Ibanez-Tallon
et al., 2003; McGrath et al., 2003; Inglis
et al., 2006; Satir and Christensen,
2007]. Motile cilia of the node also
contain the left–right dynein protein
(Dnahc11 gene, homologous to human
DNAH11), which is required for their
functional motility [Supp et al., 1997,
1999; Okada et al., 1999; McGrath et al.,
2003].
ARTICLE
Motile cilia of the node
also contain the left–right
dynein protein (Dnahc11
gene, homologous to
human DNAH11), which
is required for their
functional motility.
Recent data have provided insight
into the genetic program required for
motile ciliogenesis. Foxj1, a forkhead
transcription factor, is expressed in tissues
with motile cilia. Foxj1 is required for
induction of gene expression necessary
for motile ciliogenesis [Stubbs et al.,
2008; Yu et al., 2008] in multiple species
including zebrafish, mice, and Xenopus
[Chen et al., 1998; Brody et al., 2000;
Zhang et al., 2004; Stubbs et al., 2008; Yu
et al., 2008]. Thus, Foxj1 is acting as an
upstream regulator of cilia formation and
function at the organizer [Whitsett and
Tichelaar, 1999; Zhang et al., 2004;
Stubbs et al., 2008].
Intraflagellar transport (IFT) is
important for cilia formation, structural
function and motility, and signaling
function. It is the mechanism responsible
for delivering proteins necessary for
ciliary formation and function from the
cytoplasm of the cell to the cilia. This
process involves anterograde transport,
toward the tip of the ciliary structure,
Intraflagellar transport (IFT) is
important for cilia formation,
structural function and
motility, and signaling
function. It is the
mechanism responsible for
delivering proteins necessary
for ciliary formation and
function from the cytoplasm of
the cell to the cilia.
ARTICLE
performed by plus-end directed motor
protein complexes involving kinesins,
and retrograde transport, directed
toward the base of the cilium, carried
out by minus-end directed motor
protein complexes involving dyneins
[Rosenbaum and Witman, 2002]. Studies of loss of function in mouse models
demonstrate the necessity of these proteins for left–right patterning [Supp
et al., 1997; Nonaka et al., 1998;
Marszalek et al., 1999; Takeda et al.,
1999; Rana et al., 2004]. Recent IFT
studies in mouse have also uncovered the
critical role for cilia in signal transduction in a number of developmental
pathways including Sonic hedgehog and
Wnt pathways [Huangfu et al., 2003;
Huangfu and Anderson, 2005, 2006; Liu
et al., 2005; Davis et al., 2006; Singla and
Reiter, 2006; Corbit et al., 2008; Jopling
and Izpisua Belmonte, 2009]. Studies in
zebrafish and Xenopus have also linked
FGF signaling with the intraflagellar
pathway and thus, ciliogenesis [Hong
and Dawid, 2009; Neugebauer et al.,
2009]. New intracellular roles for
molecular motor proteins apart from
their role in ciliogenesis are also being
examined in left–right asymmetry
[Armakolas and Klar, 2007; Levin and
Palmer, 2007].
Leftward Flow Breaks Bilateral
Symmetry at the Node
In mouse, Nodal, a ligand of the TGF-b
signaling pathway, is first expressed symmetrically in crown cells surrounding the
node, followed by asymmetrical leftsided expression. The development of
asymmetric gene expression at the node is
the first molecular evidence of asymmetry and is critical for subsequent left-sided
gene expression in the LPM.
Two theories exist involving the
mechanism by which information is
transferred by the leftward flow of cilia.
The first involves secretion of morphogenetic proteins at the node into the
extracellular fluid. FGF signaling triggers the release of particles carrying
morphogens Sonic hedgehog and retinoic acid, which are forced to the left of
the node inducing a cascade of gene
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
expression [Okada et al., 2005; Hirokawa et al., 2006]. There is also evidence
that the leftward flow of extracellular
fluid causes bending of the peripheral
immotile cilia surrounding the node
[McGrath et al., 2003]. An asymmetric
calcium flux is subsequently induced and
may trigger left-sided signaling. Both of
these pathways seem likely to play a role,
but the precise mechanism by which
asymmetric Nodal expression is induced
at the node is not known.
Transfer of Asymmetric Gene
Expression From the Node to
the LPM
The role of the Nodal signal transduction pathway in vertebrate left–right
asymmetry is a common pathway in all
vertebrates studied thus far and has been
extensively described [Palmer, 2004;
Raya and Belmonte, 2004; Levin,
2005; Levin and Palmer, 2007]. The
majority of known human heterotaxy
mutations have been discovered in
this pathway using a candidate gene
approach. However, mutations within
this pathway cause heterotaxy in
a minority of cases, indicating that novel
genetic etiologies remain to be determined (Table II).
After left-sided expression of Nodal
is established at the mouse node, the
signal is propagated to the left LPM
where Nodal, in the presence of an
EGF-CFC co-factor, signals through
Type I and Type II receptors. Nodal
can activate two antagonists, Lefty-1,
expressed in the midline, and Lefty-2,
expressed in the LPM (homologous to
human LEFTYA and LEFTYB, respectively). The activation of these Nodal
antagonists limits Nodal expression and
inhibits the transfer of left-sided gene
expression across the midline of the
embryo. The role of the midline in the
establishment of left–right asymmetry
was recently reviewed [Lee and Anderson, 2008]. Pitx2, a homeobox transcription factor, is also activated by
Nodal and is asymmetrically expressed
in the LPM as well as various organs.
This molecular asymmetry is conserved
across vertebrates.
311
Signaling From the LPM to
Organ Primordial
The asymmetric expression of Pitx2 is
initiated by Nodal signaling but persists
after the disappearance of these signals in
the LPM [Shiratori et al., 2001]. Pitx2 is
involved in organogenesis in the heart,
gut, and lung and demonstrates asymmetric expression in developing organ
primordia. Recent work examining the
looping of the linear gut tube [Davis et al.,
2008; Kurpios et al., 2008], found that
Pitx2 and Isl2 act upstream of asymmetric
cellular morphology and regulate expression of adhesion molecules. Information
about cardiac specific targets during
looping morphogenesis is currently lacking and needs further investigation.
Interestingly, recent work has identified
cilia within the developing heart [Van der
Heiden et al., 2006; Slough et al., 2008]
and suggested a potential role in cardiac
development distinct from their role
in left–right asymmetry. In addition,
Interestingly, recent work has
identified cilia within the
developing heart and
suggested a potential role in
cardiac development distinct
from their role in
left–right asymmetry.
there is evidence that cilia are acting as
sensors for endothelial shear stress produced by the flow of fluid through vessels
[Iomini et al., 2004]. Preliminary work
suggests involvement of cilia in nitric
oxide production and endothelial cell
dysfunction [Van der Heiden et al., 2008;
AbouAlaiwi et al., 2009]. Further investigation into these additional roles for cilia
in the cardiovascular system may lead to a
better understanding of the pathogenesis
of heterotaxy and PCD.
New Approaches and Advantages
Using Model Organisms
Recently, new approaches in the study
of left–right asymmetry using model
312
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
ARTICLE
TABLE II. Gene Mutations Identified in Human Laterality Disorders
Gene
Heterotaxy
NODAL
ZIC3
CFC1
Mutation prevalence
Refs.
5–10%
1% in sporadic; >75% in familial X-linked
6–21%
Mohapatra et al. [2009], Roessler et al. [2008]
Ware et al. [2004]
Bamford et al. [2000], Roessler et al. [2008], Selamet Tierney
et al. [2007]
Robinson et al. [2003]
Roessler et al. [2008]
Peeters et al. [2003, 2006]
Kosaki et al. [1999a]
Karkera et al. [2007], Roessler et al. [2008]
Kosaki et al. [1999b]
Watanabe et al. [2002]
CRELD1
FOXH1
SESN1
LEFTY A
GDF1
ACVR2B
NKX2.5
PCD
DNAH5
DNAI1
<1%
Unknown
<1%
1.6%
2.1%
2.4%
Unknown
DNAI2
DNAH11
TXNDC3
RPGR
KTU
Heterotaxy þ PCD
DNAI1 or DNAH5
1.9%
Unknown
2.1%
Unknown
1.8%
organisms have emerged. Given that the
core components of the Nodal signaling
pathway are conserved across species, it is
useful to exploit the advantages that each
model organism provides to study the
establishment of left–right asymmetry.
For example, a recent zebrafish mutagenesis study [Zhang et al., 2009] using
forward genetic screening followed by
massively parallel sequencing identified
a gene, Megf8, involved in the propagation of the Nodal signal from the node to
the LPM. This is a relatively fast and cost
efficient method to identify new pathways and genes implicated in left–right
development. Additionally, Xenopus
offers the advantage of combinatorial
knockdown of genes using morpholinos
as well as right- and left-side specific
knockdown of genes. These processes
can be observed and directly manipulated with dorsal explants in which
unidirectional flow can be established.
The advantages of this system have
recently been reviewed [Levin and
Palmer, 2007; Blum et al., 2009]. While
differences in left–right patterning
15–28%
2–10%
58%
Failly et al. [2009], Hornef et al. [2006], Olbrich et al. [2002]
Failly et al. [2008], Zariwala et al. [2001], Zariwala et al. [2006]
Guichard et al. [2001], Pennarun et al. [1999]
Loges et al. [2008]
Bartoloni et al. [2002], Schwabe et al. [2008]
Duriez et al. [2007]
Moore et al. [2006]
Omran et al. [2008]
Kennedy et al. [2007]
exist between model organisms, there
are also core conserved mechanisms
involved in the establishment of asymmetry, and exploiting the strengths of a
variety of model organisms will
undoubtedly uncover new pathways as
well as new roles for previously discovered genes.
GENETICS OF PCD
AND HETEROTAXY
In the majority of cases, situs inversus
associated with PCD is an autosomal
recessive condition. The differential
would include other ciliopathies in
which situs inversus can be found,
including Bardet–Biedl syndrome.
Heterotaxy most often occurs as a
sporadic condition. Complex inheritance or autosomal dominant inheritance with reduced penetrance and
variable expressivity are presumed
genetic mechanisms. Familial clustering
of heterotaxy has been documented,
with pedigrees suggestive of autosomal
recessive and autosomal dominant
inheritance [Vitale et al., 2001; Belmont
et al., 2004; Zhu et al., 2006; Wessels
et al., 2008]. X-linked inheritance is well
documented in heterotaxy and is caused
by mutations in ZIC3. A large number of
genetic syndromes and chromosome
abnormalities have been associated
with heterotaxy, including aneuploidies,
complex chromosomal rearrangements,
and microdeletions [Bisgrove et al.,
2003; Ware and Belmont, 2008; Song
et al., 2009]. For example, patients with
trisomy 13 or trisomy 18 have been
reported. A number of submicroscopic
chromosomal deletions, including
22q11.2 (DiGeorge/VCFS syndrome),
have been identified in patients with
heterotaxy. Bisgrove et al. [2003] review
unbalanced translocations, terminal
deletions, inversions, and more complex
chromosomal rearrangements associated
with heterotaxy. Analysis of genes
located within submicroscopic chromosomal imbalances in patients with abnormal left–right asymmetry should be a
useful tool in uncovering novel genes
and pathways in laterality defects.
ARTICLE
X-Linked Inheritance
An X-linked form of PCD has been
described in association with retinitis
pigmentosa, resulting from mutations in
RPGR (OMIM #300455). The visual
abnormalities are associated with hearing loss, sinusitis, and chronic recurrent
respiratory tract infections, and abnormalities of the ciliary axoneme have been
identified by electron microscopy [Zito
et al., 2003; Moore et al., 2006]. The Xlinked form of heterotaxy, HTX-1
(OMIM #306955) is caused by mutations in a zinc finger transcription factor,
ZIC3 [Ferrero et al., 1997; Gebbia et al.,
1997]. Approximately 1% of sporadic
heterotaxy cases (male and female)
are caused by mutations in ZIC3, and
affected females have been described
with point mutations or with chromosomal translocations [Megarbane et al.,
2000; Ware et al., 2004; Fritz et al., 2005;
Tzschach et al., 2006; Chhin et al.,
2007]. In X-linked pedigrees, ZIC3
mutations are commonly identified
(Table II). Clinical testing is available.
The mutations cause loss of function
and, in some cases, result in abnormal
subcellular localization and trafficking
[Bedard et al., 2007]. Loss of function of
ZIC3 has been correlated with a range
of phenotypes ranging from classic
heterotaxy to isolated cardiovascular
malformations typical of abnormal heart
looping, such as double outlet right
ventricle, L-transposition of the great
arteries, and ventricular inversion.
There is evidence in model organisms
that ZIC3 acts upstream of Nodal
signaling at the node, but its precise
developmental function is not yet
known [Purandare et al., 2002; Ware
et al., 2006].
Autosomal Dominant Inheritance
Heterotaxy patients without mutations
in ZIC3 have been screened for mutations in genes involved in the conserved
Nodal signal transduction pathway.
Given the importance of the Nodal
pathway in establishing left–right asymmetry, it is not surprising that mutations
in components of this pathway, including NODAL itself, have been identified
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
in human heterotaxy (Table II) [Kosaki
et al., 1999a,b; Bamford et al., 2000;
Goldmuntz et al., 2002; Selamet Tierney et al., 2007; Roessler et al., 2008;
Mohapatra et al., 2009].
Mutations have been identified in
genes encoding the ligand (NODAL),
ligand co-receptor (CFC-1), receptor
(ACVRIIB), transcriptional co-activator
(FOXH1), and midline inhibitor
(LEFTYA) within the Nodal signal
transduction pathway (Table II).
Recently, NODAL variants were investigated in 269 patients with heterotaxy
or isolated cardiovascular mutations
thought to be associated with irregular
looping of the heart. Missense mutations
were observed in 14 of the unrelated
patients [Mohapatra et al., 2009]. Functional analysis of the mutant proteins
showed a decrease in Nodal signaling.
Similarly, functional analysis of mutations in Cryptic, a gene encoding an
epidermal growth factor family protein,
CFC1, which functions as a NODAL
co-receptor, revealed abnormal cellular
localization of the mutant protein
[Bamford et al., 2000]. In addition,
mutations in CFC1 have been identified
in patients with transposition of the
great arteries but without extra-cardiac
anomalies [Goldmuntz et al., 2002].
ACVRIIB mutations were identified in
3 of 126 patients with left–right anomalies and mutations in LEFTYA were
discovered in 2 patients [Kosaki et al.,
1999a,b]. In the latter case, each
patient inherited the mutant allele
from an unaffected carrier parent, indicating incomplete penetrance. Candidate gene analysis has also focused
on GDF1, a gene expressed in the
node encoding a TGF-b ligand. In
375 patients, 8 potential disease-causing
mutations were discovered [Karkera
et al., 2007].
With over 100 candidate genes
identified through mouse models of
left–right patterning defects, it is likely
that significant genetic heterogeneity
will be found in human heterotaxy. To
date, the majority of genes identified
have either not yet been tested in larger
heterotaxy populations (e.g., NKX2.5,
CRELD1), or have been found to have
mutations at low frequency [Watanabe
313
et al., 2002; Robinson et al., 2003]. For
example, positional cloning of a region
involved in a reciprocal translocation in
one patient identified SESN1, a gene
involved in left–right patterning. Functional analysis of this protein revealed
that it plays a role in activating Nodal
signaling. However, the prevalence of
disease causing mutations in this gene is
less than 1% based on an initial screen of a
heterotaxy cohort [Peeters et al., 2003,
2006].
Efforts are ongoing to identify novel
genes that cause or contribute to the
heterotaxy phenotype. Mapping studies
in two different families with autosomal
dominant inheritance with reduced
penetrance [Vitale et al., 2001; Wessels
et al., 2008] have identified a locus on
chromosome 6p encompassing approximately 12 Mb and a small number of
strong candidate genes. Interestingly, two
of the candidates are dynein heavy chain
genes, while another is a kinesin gene.
Autosomal Recessive Inheritance
PCD disorders are characterized by
abnormalities of ciliary structure and
function and are most commonly autosomal recessive. Mutations in DNAH5
are the most commonly identified cause
In addition, it has recently
been shown that patients with
PCD have a higher risk for
congenital heart disease,
similar to patients with
heterotaxy, or situs
ambiguus.
of PCD [Olbrich et al., 2002], with
mutations in DNAI1 [Pennarun et al.,
1999] and DNAH11 [Pan et al., 1998;
Bartoloni et al., 2002] also contributing.
All are outer dynein arm components
which are essential for ciliary function at
the node. Mutations in these genes result
in randomized situs, leading to situs
inversus in approximately 50% of
314
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
patients [Noone et al., 2004]. In addition, it has recently been shown that
patients with PCD have a higher risk for
congenital heart disease, similar to
patients with heterotaxy, or situs ambiguus [Kennedy et al., 2007].
Complex Inheritance
Approximately 10% of patients with
heterotaxy have a family history of a
close relative with a congenital heart
defect. To date, the majority of mutations identified have been shown to have
reduced penetrance and variable expressivity, indicating multifactorial causation.
X-linked heterotaxy, caused by
mutations in ZIC3, is the best understood genetic cause of heterotaxy. Interestingly, mutations in this gene can cause
classic heterotaxy or isolated congenital
heart defects. In one family, three of nine
female carriers exhibited situs inversus
[Gebbia et al., 1997; Ware et al., 2004].
In vitro analyses of these ZIC3 mutations
indicate similar levels of functional
abnormalities, suggesting that the range
of phenotypes results from genetic
modifiers, environmental modifiers,
epigenetic effects, or developmental
stochasticity. There are reports to support each of these mechanisms. For
example, in a small number of cases,
mutations in two or more genes within
the Nodal signal transduction pathway,
or in NODAL and ZIC3 in a female
patient, have been identified. In addition, a common NODAL polymorphism that reduces gene activity has
been identified. These findings support
the hypothesis that common or rare
deleterious genetic variants within
developmental pathways may disrupt
signaling in a synergistic or combinatorial fashion to cause congenital anomalies [Gebbia et al., 1997; Roessler et al.,
2008]. Environmental modifiers such as
maternal diabetes, maternal cocaine use,
and monozygotic twinning have all been
associated with heterotaxy spectrum
defects [Kuehl and Loffredo, 2002].
Stochastic levels of Nodal expression
have been reported in inbred mouse
lines deficient for Gdf3, a TGF-b ligand
that acts in a Nodal-related pathway
[Chen et al., 2006]. Taken together,
these mechanisms likely account for the
significant degree of the variability
within the heterotaxy/congenital heart
disease/PCD population.
CONCLUSIONS AND
FUTURE DIRECTIONS
The molecular players involved in PCD
and heterotaxy are being discovered at a
rapid pace and there is increasing
recognition of the overlap between these
two categories of laterality disorders.
Over 100 genes have been identified as
important in left–right asymmetry in
animal models. Combined with recent
The molecular players involved
in PCD and heterotaxy are
being discovered at a rapid pace
and there is increasing
recognition of the overlap
between these two categories of
laterality disorders. Over
100 genes have been identified
as important in left–right
asymmetry in animal models.
studies on the ciliome, the number of
candidates for laterality disorders is quite
large [Inglis et al., 2006]. This heterogeneity, combined with a prediction of
reduced penetrance and variable expressivity, makes clinical molecular diagnostics challenging. Further clinical
insight into the relationship between
situs inversus, situs ambiguus, and
isolated cardiovascular malformations
within the heterotaxy spectrum will be
important for clinical management and
diagnosis. An improved comprehension
of the developmental basis of disease and
the interactions of pathways involved in
the establishment of proper left–right
asymmetry is needed for a fully integrated understanding of phenotypic
expression. Recent improvements in
sequencing cost and throughput will
improve the ability to interrogate
ARTICLE
gene gene interactions by facilitating
pathway approaches to screening. Future
studies will focus on the challenges
inherent in the interpretation and functional analysis of the sequence variation
identified from genomic data in order to
identify combinations of deleterious
variants. The long-term challenge is
to translate a functional understanding
of developmental pathway interactions
into a prediction of phenotypic effects
and provision of reliable risk estimates
for families.
REFERENCES
AbouAlaiwi WA, Takahashi M, Mell BR, Jones
TJ, Ratnam S, Kolb RJ, Nauli SM. 2009.
Ciliary polycystin-2 is a mechanosensitive
calcium channel involved in nitric oxide
signaling cascades. Circ Res 104:860–
869.
Afzelius BA. 1976. A human syndrome caused by
immotile cilia. Science 193:317–319.
Armakolas A, Klar AJ. 2007. Left-right dynein
motor implicated in selective chromatid
segregation in mouse cells. Science 315:
100–101.
Aw S, Levin M. 2009. Is left-right asymmetry a
form of planar cell polarity? Development
136:355–366.
Bamford RN, Roessler E, Burdine RD, Saplakoglu U, dela Cruz J, Splitt M, Goodship JA,
Towbin J, Bowers P, Ferrero GB, Marino B,
Schier AF, Shen MM, Muenke M, Casey B.
2000. Loss-of-function mutations in the
EGF-CFC gene CFC1 are associated with
human left-right laterality defects. Nat
Genet 26:365–369.
Bartoloni L, Blouin JL, Pan Y, Gehrig C, Maiti
AK, Scamuffa N, Rossier C, Jorissen M,
Armengot M, Meeks M, Mitchison
HM, Chung EM, Delozier-Blanchet
CD, Craigen WJ, Antonarakis SE. 2002.
Mutations in the DNAH11 (axonemal
heavy chain dynein type 11) gene cause
one form of situs inversus totalis and most
likely primary ciliary dyskinesia. Proc Natl
Acad Sci USA 99:10282–10286.
Bedard JE, Purnell JD, Ware SM. 2007. Nuclear
import and export signals are essential for
proper cellular trafficking and function of
ZIC3. Hum Mol Genet 16:187–198.
Belmont JW, Mohapatra B, Towbin JA, Ware SM.
2004. Molecular genetics of heterotaxy
syndromes. Curr Opin Cardiol 19:216–
220.
Bisgrove BW, Morelli SH, Yost HJ. 2003.
Genetics of human laterality disorders:
Insights from vertebrate model systems.
Annu Rev Genomics Hum Genet 4:1–32.
Blum M, Beyer T, Weber T, Vick P, Andre P,
Bitzer E, Schweickert A. 2009. Xenopus, an
ideal model system to study vertebrate
left-right asymmetry. Dev Dyn 238:1215–
1225.
Brody SL, Yan XH, Wuerffel MK, Song SK,
Shapiro SD. 2000. Ciliogenesis and leftright axis defects in forkhead factor HFH-4-
ARTICLE
null mice. Am J Respir Cell Mol Biol 23:
45–51.
Chen J, Knowles HJ, Hebert JL, Hackett BP.
1998. Mutation of the mouse hepatocyte
nuclear factor/forkhead homologue 4 gene
results in an absence of cilia and random
left-right asymmetry. J Clin Invest 102:
1077–1082.
Chen C, Ware SM, Sato A, Houston-Hawkins
DE, Habas R, Matzuk MM, Shen MM,
Brown CW. 2006. The Vg1-related protein
Gdf3 acts in a Nodal signaling pathway in
the pre-gastrulation mouse embryo. Development 133:319–329.
Chhin B, Hatayama M, Bozon D, Ogawa M,
Schon P, Tohmonda T, Sassolas F, Aruga J,
Valard AG, Chen SC, Bouvagnet P. 2007.
Elucidation of penetrance variability of a
ZIC3 mutation in a family with complex
heart defects and functional analysis of ZIC3
mutations in the first zinc finger domain.
Hum Mutat 28:563–570.
Corbit KC, Shyer AE, Dowdle WE, Gaulden J,
Singla V, Chen MH, Chuang PT, Reiter JF.
2008. Kif3a constrains beta-catenindependent Wnt signalling through dual
ciliary and non-ciliary mechanisms. Nat
Cell Biol 10:70–76.
Davis EE, Brueckner M, Katsanis N. 2006. The
emerging complexity of the vertebrate
cilium: New functional roles for an ancient
organelle. Dev Cell 11:9–19.
Davis NM, Kurpios NA, Sun X, Gros J, Martin JF,
Tabin CJ. 2008. The chirality of gut rotation
derives from left-right asymmetric changes
in the architecture of the dorsal mesentery.
Dev Cell 15:134–145.
Duriez B, Duquesnoy P, Escudier E, Bridoux
AM, Escalier D, Rayet I, Marcos E, Vojtek
AM, Bercher JF, Amselem S. 2007. A
common variant in combination with a
nonsense mutation in a member of the
thioredoxin family causes primary ciliary
dyskinesia. Proc Natl Acad Sci USA 104:
3336–3341.
Essner JJ, Vogan KJ, Wagner MK, Tabin CJ, Yost
HJ, Brueckner M. 2002. Conserved function for embryonic nodal cilia. Nature 418:
37–38.
Failly M, Saitta A, Munoz A, Falconnet E, Rossier
C, Santamaria F, de Santi MM, Lazor R,
DeLozier-Blanchet CD, Bartoloni L, Blouin
JL. 2008. DNAI1 mutations explain only 2%
of primary ciliary dykinesia. Respiration
76:198–204.
Failly M, Bartoloni L, Letourneau A, Munoz A,
Falconnet E, Rossier C, de Santi MM,
Santamaria F, Sacco O, DeLozier-Blanchet
CD, Lazor R, Blouin JL. 2009. Mutations in
DNAH5 account for only 15% of a nonpreselected cohort of patients with primary
ciliary dyskinesia. J Med Genet 46:281–
286.
Ferrero GB, Gebbia M, Pilia G, Witte D, Peier A,
Hopkin RJ, Craigen WJ, Shaffer LG,
Schlessinger D, Ballabio A, Casey B. 1997.
A submicroscopic deletion in Xq26 associated with familial situs ambiguus. Am
J Hum Genet 61:395–401.
Fritz B, Kunz J, Knudsen GP, Louwen F,
Kennerknecht I, Eiben B, Orstavik KH,
Friedrich U, Rehder H. 2005. Situs ambiguus in a female fetus with balanced (X;21)
translocation—Evidence for functional
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
nullisomy of the ZIC3 gene? Eur J Hum
Genet 13:34–40.
Gebbia M, Ferrero GB, Pilia G, Bassi MT,
Aylsworth A, Penman-Splitt M, Bird LM,
Bamforth JS, Burn J, Schlessinger D, Nelson
DL, Casey B. 1997. X-linked situs
abnormalities result from mutations in
ZIC3. Nat Genet 17:305–308.
Goldmuntz E, Bamford R, Karkera JD, dela Cruz
J, Roessler E, Muenke M. 2002. CFC1
mutations in patients with transposition of
the great arteries and double-outlet right
ventricle. Am J Hum Genet 70:776–780.
Gros J, Feistel K, Viebahn C, Blum M, Tabin CJ.
2009. Cell movements at Hensen’s node
establish left/right asymmetric gene expression in the chick. Science 324:941–944.
Guichard C, Harricane MC, Lafitte JJ, Godard P,
Zaegel M, Tack V, Lalau G, Bouvagnet P.
2001. Axonemal dynein intermediate-chain
gene (DNAI1) mutations result in situs
inversus and primary ciliary dyskinesia
(Kartagener syndrome). Am J Hum Genet
68:1030–1035.
Hirokawa N, Tanaka Y, Okada Y, Takeda S. 2006.
Nodal flow and the generation of left-right
asymmetry. Cell 125:33–45.
Hong SK, Dawid IB. 2009. FGF-dependent
left-right asymmetry patterning in zebrafish
is mediated by Ier2 and Fibp1. Proc Natl
Acad Sci USA 106:2230–2235.
Hornef N, Olbrich H, Horvath J, Zariwala MA,
Fliegauf M, Loges NT, Wildhaber J, Noone
PG, Kennedy M, Antonarakis SE, Blouin
JL, Bartoloni L, Nusslein T, Ahrens P, Griese
M, Kuhl H, Sudbrak R, Knowles MR,
Reinhardt R, Omran H. 2006. DNAH5
mutations are a common cause of primary
ciliary dyskinesia with outer dynein arm
defects. Am J Respir Crit Care Med 174:
120–126.
Huangfu D, Anderson KV. 2005. Cilia and
Hedgehog responsiveness in the mouse.
Proc Natl Acad Sci USA 102:11325–11330.
Huangfu D, Anderson KV. 2006. Signaling
from Smo to Ci/Gli: Conservation and
divergence of Hedgehog pathways from
Drosophila to vertebrates. Development
133:3–14.
Huangfu D, Liu A, Rakeman AS, Murcia NS,
Niswander L, Anderson KV. 2003. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426:83–
87.
Ibanez-Tallon I, Heintz N, Omran H. 2003. To
beat or not to beat: Roles of cilia in
development and disease. Hum Mol Genet
12:R27–R35.
Inglis PN, Boroevich KA, Leroux MR. 2006.
Piecing together a ciliome. Trends Genet
22:491–500.
Iomini C, Tejada K, Mo W, Vaananen H, Piperno
G. 2004. Primary cilia of human endothelial
cells disassemble under laminar shear stress.
J Cell Biol 164:811–817.
Jacobs JP, Anderson RH, Weinberg PM, Walters
HLIII, Tchervenkov CI, Del Duca D,
Franklin RC, Aiello VD, Beland MJ, Colan
SD, Gaynor JW, Krogmann ON, Kurosawa
H, Maruszewski B, Stellin G, Elliott MJ.
2007. The nomenclature, definition and
classification of cardiac structures in the
setting of heterotaxy. Cardiol Young 17:1–
28.
315
Jopling C, Izpisua Belmonte JC. 2009. Cilia—
where two Wnts collide. Zebrafish 6:15–
19.
Karkera JD, Lee JS, Roessler E, Banerjee-Basu S,
Ouspenskaia MV, Mez J, Goldmuntz E,
Bowers P, Towbin J, Belmont JW, Baxevanis
AD, Schier AF, Muenke M. 2007. Loss-offunction mutations in growth differentiation
factor-1 (GDF1) are associated with congenital heart defects in humans. Am J Hum
Genet 81:987–994.
Kartagener ZM. 1933. Pathogenesis der Bronchiektasien bei Situs viscerum inversus.
Beitr Klin Tuberk 83:489–501.
Kennedy MP, Omran H, Leigh MW, Dell S,
Morgan L, Molina PL, Robinson BV,
Minnix SL, Olbrich H, Severin T, Ahrens
P, Lange L, Morillas HN, Noone PG,
Zariwala MA, Knowles MR. 2007. Congenital heart disease and other heterotaxic
defects in a large cohort of patients with
primary ciliary dyskinesia. Circulation
115:2814–2821.
Kosaki K, Bassi MT, Kosaki R, Lewin M,
Belmont J, Schauer G, Casey B. 1999a.
Characterization and mutation analysis of
human LEFTY A and LEFTY B, homologues of murine genes implicated in leftright axis development. Am J Hum Genet
64:712–721.
Kosaki R, Gebbia M, Kosaki K, Lewin M, Bowers
P, Towbin JA, Casey B. 1999b. Left-right
axis malformations associated with mutations in ACVR2B, the gene for human
activin receptor type IIB. Am J Med Genet
82:70–76.
Krebs LT, Iwai N, Nonaka S, Welsh IC, Lan Y,
Jiang R, Saijoh Y, O’Brien TP, Hamada H,
Gridley T. 2003. Notch signaling regulates
left-right asymmetry determination by
inducing Nodal expression. Genes Dev 17:
1207–1212.
Kuehl KS, Loffredo C. 2002. Risk factors for
heart disease associated with abnormal
sidedness. Teratology 66:242–248.
Kurpios NA, Ibanes M, Davis NM, Lui W, Katz
T, Martin JF, Belmonte JC, Tabin CJ. 2008.
The direction of gut looping is established
by changes in the extracellular matrix and in
cell:cell adhesion. Proc Natl Acad Sci USA
105:8499–8506.
Lee JD, Anderson KV. 2008. Morphogenesis of
the node and notochord: The cellular basis
for the establishment and maintenance of
left-right asymmetry in the mouse. Dev
Dyn 237:3464–3476.
Leigh MW, Zariwala MA, Knowles MR. 2009.
Primary ciliary dyskinesia: Improving the
diagnostic approach. Curr Opin Pediatr 21:
320–325.
Levin M. 2005. Left-right asymmetry in embryonic development: A comprehensive review.
Mech Dev 122:3–25.
Levin M, Palmer AR. 2007. Left-right patterning
from the inside out: Widespread evidence
for intracellular control. Bioessays 29:271–
287.
Lin AE, Ticho BS, Houde K, Westgate MN,
Holmes LB. 2000. Heterotaxy: Associated
conditions and hospital-based prevalence in
newborns. Genet Med 2:157–172.
Liu A, Wang B, Niswander LA. 2005. Mouse
intraflagellar transport proteins regulate
both the activator and repressor functions
316
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
of Gli transcription factors. Development
132:3103–3111.
Loges NT, Olbrich H, Fenske L, Mussaffi H,
Horvath J, Fliegauf M, Kuhl H, Baktai G,
Peterffy E, Chodhari R, Chung EM, Rutman A, O’Callaghan C, Blau H, Tiszlavicz
L, Voelkel K, Witt M, Zietkiewicz E,
Neesen J, Reinhardt R, Mitchison HM,
Omran H. 2008. DNAI2 mutations cause
primary ciliary dyskinesia with defects in the
outer dynein arm. Am J Hum Genet 83:
547–558.
Marszalek JR, Ruiz-Lozano P, Roberts E, Chien
KR, Goldstein LS. 1999. Situs inversus and
embryonic ciliary morphogenesis defects in
mouse mutants lacking the KIF3A subunit
of kinesin-II. Proc Natl Acad Sci USA 96:
5043–5048.
McGrath J, Somlo S, Makova S, Tian X,
Brueckner M. 2003. Two populations of
node monocilia initiate left-right asymmetry
in the mouse. Cell 114:61–73.
Megarbane A, Salem N, Stephan E, Ashoush R,
Lenoir D, Delague V, Kassab R, Loiselet J,
Bouvagnet P. 2000. X-linked transposition
of the great arteries and incomplete penetrance among males with a nonsense
mutation in ZIC3. Eur J Hum Genet 8:
704–708.
Mohapatra B, Casey B, Li H, Ho-Dawson T,
Smith L, Fernbach SD, Molinari L,
Niesh SR, Jefferies JL, Craigen WJ,
Towbin JA, Belmont JW, Ware SM.
2009. Identification and functional characterization of NODAL rare variants in
heterotaxy and isolated cardiovascular
malformations. Hum Mol Genet 18:861–
871.
Moore A, Escudier E, Roger G, Tamalet A,
Pelosse B, Marlin S, Clement A, Geremek
M, Delaisi B, Bridoux AM, Coste A, Witt
M, Duriez B, Amselem S. 2006. RPGR is
mutated in patients with a complex X linked
phenotype combining primary ciliary dyskinesia and retinitis pigmentosa. J Med
Genet 43:326–333.
Neugebauer JM, Amack JD, Peterson AG,
Bisgrove BW, Yost HJ. 2009. FGF signalling
during embryo development regulates cilia
length in diverse epithelia. Nature 458:651–
654.
Nonaka S, Tanaka Y, Okada Y, Takeda S, Harada
A, Kanai Y, Kido M, Hirokawa N. 1998.
Randomization of left-right asymmetry due
to loss of nodal cilia generating leftward flow
of extraembryonic fluid in mice lacking
KIF3B motor protein. Cell 95:829–
837.
Nonaka S, Shiratori H, Saijoh Y, Hamada H.
2002. Determination of left-right patterning
of the mouse embryo by artificial nodal flow.
Nature 418:96–99.
Noone PG, Leigh MW, Sannuti A, Minnix SL,
Carson JL, Hazucha M, Zariwala MA,
Knowles MR. 2004. Primary ciliary dyskinesia: Diagnostic and phenotypic features. Am J Respir Crit Care Med 169:459–
467.
Okada Y, Nonaka S, Tanaka Y, Saijoh Y, Hamada
H, Hirokawa N. 1999. Abnormal nodal
flow precedes situs inversus in iv and inv
mice. Mol Cell 4:459–468.
Okada Y, Takeda S, Tanaka Y, Belmonte JC,
Hirokawa N. 2005. Mechanism of nodal
flow: A conserved symmetry breaking event
in left-right axis determination. Cell 121:
633–644.
Olbrich H, Haffner K, Kispert A, Volkel A,
Volz A, Sasmaz G, Reinhardt R, Hennig S,
Lehrach H, Konietzko N, Zariwala M,
Noone PG, Knowles M, Mitchison HM,
Meeks M, Chung EM, Hildebrandt F,
Sudbrak R, Omran H. 2002. Mutations in
DNAH5 cause primary ciliary dyskinesia
and randomization of left-right asymmetry.
Nat Genet 30:143–144.
Omran H, Kobayashi D, Olbrich H, Tsukahara T,
Loges NT, Hagiwara H, Zhang Q,
Leblond G, O’Toole E, Hara C, Mizuno
H, Kawano H, Fliegauf M, Yagi T,
Koshida S, Miyawaki A, Zentgraf H,
Seithe H, Reinhardt R, Watanabe Y,
Kamiya R, Mitchell DR, Takeda H. 2008.
Ktu/PF13 is required for cytoplasmic
pre-assembly of axonemal dyneins. Nature
456:611–616.
Palmer AR. 2004. Symmetry breaking and the
evolution of development. Science 306:
828–833.
Pan Y, McCaskill CD, Thompson KH, Hicks J,
Casey B, Shaffer LG, Craigen WJ. 1998.
Paternal isodisomy of chromosome 7 associated with complete situs inversus and
immotile cilia. Am J Hum Genet 62:
1551–1555.
Peeters H, Debeer P, Bairoch A, Wilquet V,
Huysmans C, Parthoens E, Fryns JP, Gewillig M, Nakamura Y, Niikawa N, Van de Ven
W, Devriendt K. 2003. PA26 is a candidate
gene for heterotaxia in humans: Identification of a novel PA26-related gene family in
human and mouse. Hum Genet 112:573–
580.
Peeters H, Voz ML, Verschueren K, De Cat B,
Pendeville H, Thienpont B, Schellens A,
Belmont JW, David G, Van De Ven WJ,
Fryns JP, Gewillig M, Huylebroeck D, Peers
B, Devriendt K. 2006. Sesn1 is a novel gene
for left-right asymmetry and mediating
nodal signaling. Hum Mol Genet 15:
3369–3377.
Pennarun G, Escudier E, Chapelin C, Bridoux
AM, Cacheux V, Roger G, Clement A,
Goossens M, Amselem S, Duriez B. 1999.
Loss-of-function mutations in a human gene
related to Chlamydomonas reinhardtii
dynein IC78 result in primary ciliary
dyskinesia. Am J Hum Genet 65:1508–
1519.
Przemeck GK, Heinzmann U, Beckers J, Hrabe
de Angelis M. 2003. Node and midline
defects are associated with left-right
development in Delta1 mutant embryos.
Development 130:3–13.
Purandare SM, Ware SM, Kwan KM, Gebbia M,
Bassi MT, Deng JM, Vogel H, Behringer
RR, Belmont JW, Casey B. 2002. A
complex syndrome of left-right axis, central
nervous system and axial skeleton defects in
Zic3 mutant mice. Development 129:
2293–2302.
Rana AA, Barbera JP, Rodriguez TA, Lynch D,
Hirst E, Smith JC, Beddington RS. 2004.
Targeted deletion of the novel cytoplasmic
dynein mD2LIC disrupts the embryonic
organiser, formation of the body axes and
specification of ventral cell fates. Development 131:4999–5007.
ARTICLE
Raya A, Belmonte JC. 2004. Sequential transfer
of left-right information during vertebrate
embryo development. Curr Opin Genet
Dev 14:575–581.
Robinson SW, Morris CD, Goldmuntz E, Reller
MD, Jones MA, Steiner RD, Maslen CL.
2003. Missense mutations in CRELD1 are
associated with cardiac atrioventricular
septal defects. Am J Hum Genet 72:1047–
1052.
Roessler E, Ouspenskaia MV, Karkera JD, Velez JI,
Kantipong A, Lacbawan F, Bowers P,
Belmont JW, Towbin JA, Goldmuntz E,
Feldman B, Muenke M. 2008. Reduced
NODAL signaling strength via mutation of
several pathway members including FOXH1
is linked to human heart defects and
holoprosencephaly. Am J Hum Genet 83:
18–29.
Rosenbaum JL, Witman GB. 2002. Intraflagellar
transport. Nat Rev Mol Cell Biol 3:813–
825.
Satir P, Christensen ST. 2007. Overview of
structure and function of mammalian cilia.
Annu Rev Physiol 69:377–400.
Schwabe GC, Hoffmann K, Loges NT, Birker D,
Rossier C, de Santi MM, Olbrich H,
Fliegauf M, Failly M, Liebers U, Collura
M, Gaedicke G, Mundlos S, Wahn U,
Blouin JL, Niggemann B, Omran H,
Antonarakis SE, Bartoloni L. 2008. Primary
ciliary dyskinesia associated with normal
axoneme ultrastructure is caused by
DNAH11 mutations. Hum Mutat 29:289–
298.
Selamet Tierney ES, Marans Z, Rutkin MB,
Chung WK. 2007. Variants of the CFC1
gene in patients with laterality defects
associated with congenital cardiac disease.
Cardiol Young 17:268–274.
Shiratori H, Sakuma R, Watanabe M, Hashiguchi
H, Mochida K, Sakai Y, Nishino J, Saijoh Y,
Whitman M, Hamada H. 2001. Two-step
regulation of left-right asymmetric expression of Pitx2: Initiation by nodal signaling
and maintenance by Nkx2. Mol Cell 7:
137–149.
Singla V, Reiter JF. 2006. The primary cilium as
the cell’s antenna: Signaling at a sensory
organelle. Science 313:629–633.
Slough J, Cooney L, Brueckner M. 2008.
Monocilia in the embryonic mouse heart
suggest a direct role for cilia in cardiac
morphogenesis. Dev Dyn 237:2304–2314.
Song MS, Hu A, Dyhamenahali U, Chitayat D,
Winsor EJ, Ryan G, Smallhorn J, Barrett J,
Yoo SJ, Hornberger LK. 2009. Extracardiac
lesions and chromosomal abnormalities
associated with major fetal heart defects:
Comparison of intrauterine, postnatal and
postmortem diagnoses. Ultrasound Obstet
Gynecol 33:552–559.
Stubbs JL, Oishi I, Izpisua Belmonte JC, Kintner C.
2008. The forkhead protein Foxj1 specifies
node-like cilia in Xenopus and zebrafish
embryos. Nat Genet 40:1454–1460.
Supp DM, Witte DP, Potter SS, Brueckner M.
1997. Mutation of an axonemal dynein
affects left-right asymmetry in inversus
viscerum mice. Nature 389:963–966.
Supp DM, Brueckner M, Kuehn MR, Witte DP,
Lowe LA, McGrath J, Corrales J, Potter SS.
1999. Targeted deletion of the ATP binding
domain of left-right dynein confirms its
ARTICLE
role in specifying development of left-right
asymmetries. Development 126: 5495–5504.
Takeda S, Yonekawa Y, Tanaka Y, Okada Y,
Nonaka S, Hirokawa N. 1999. Left-right
asymmetry and kinesin superfamily protein
KIF3A: New insights in determination of
laterality and mesoderm induction by
kif3A-/- mice analysis. J Cell Biol 145:
825–836.
Takeuchi JK, Lickert H, Bisgrove BW, Sun X,
Yamamoto M, Chawengsaksophak K, Hamada H, Yost HJ, Rossant J, Bruneau BG.
2007. Baf60c is a nuclear Notch signaling
component required for the establishment of
left-right asymmetry. Proc Natl Acad Sci
USA 104:846–851.
Tzschach A, Hoeltzenbein M, Hoffmann K,
Menzel C, Beyer A, Ocker V, Wurster G,
Raynaud M, Ropers HH, Kalscheuer V,
Heilbronner H. 2006. Heterotaxy and
cardiac defect in a girl with chromosome
translocation t(X;1)(q26;p13.1) and involvement of ZIC3. Eur J Hum Genet 14:1317–
1320.
Van der Heiden K, Groenendijk BC, Hierck BP,
Hogers B, Koerten HK, Mommaas AM,
Gittenberger-de Groot AC, Poelmann RE.
2006. Monocilia on chicken embryonic
endocardium in low shear stress areas. Dev
Dyn 235:19–28.
Van der Heiden K, Hierck BP, Krams R, de Crom
R, Cheng C, Baiker M, Pourquie MJ,
Alkemade FE, DeRuiter MC, Gittenberger-de Groot AC, Poelmann RE. 2008.
Endothelial primary cilia in areas of disturbed flow are at the base of atherosclerosis.
Atherosclerosis 196:542–550.
Vandenberg LN, Levin M. 2009. Perspectives and
open problems in the early phases of leftright patterning. Semin Cell Dev Biol 20:
456–463.
Vitale E, Brancolini V, De Rienzo A, Bird L,
Allada V, Sklansky M, Chae CU, Ferrero
GB, Weber J, Devoto M, Casey B. 2001.
Suggestive linkage of situs inversus and other
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
left-right axis anomalies to chromosome 6p.
J Med Genet 38:182–185.
Ware S, Belmont J. 2008. ZIC3, CFC1,
ACVR2B, LEFTY2 and the visceral
heterotaxies. In: Epstein C, Erickson R,
Wynshaw-Boris A, editors. Inborn errors
of development: The molecular basis of
clinical disorders of morphogenesis. New
York: Oxford University Press. pp 373–382.
Ware SM, Peng J, Zhu L, Fernbach S, Colicos S,
Casey B, Towbin J, Belmont JW. 2004.
Identification and functional analysis of
ZIC3 mutations in heterotaxy and related
congenital heart defects. Am J Hum Genet
74:93–105.
Ware SM, Harutyunyan KG, Belmont JW. 2006.
Heart defects in X-linked heterotaxy:
Evidence for a genetic interaction of Zic3
with the nodal signaling pathway. Dev Dyn
235:1631–1637.
Watanabe Y, Benson DW, Yano S, Akagi T,
Yoshino M, Murray JC. 2002. Two novel
frameshift mutations in NKX2.5 result in
novel features including visceral inversus and
sinus venosus type ASD. J Med Genet
39:807–811.
Wessels MW, De Graaf BM, Cohen-Overbeek
TE, Spitaels SE, de Groot-de Laat LE, Ten
Cate FJ, Frohn-Mulder IF, de Krijger R,
Bartelings MM, Essed N, Wladimiroff
JW, Niermeijer MF, Heutink P, Oostra
BA, Dooijes D, Bertoli-Avella AM,
Willems PJ. 2008. A new syndrome with
noncompaction cardiomyopathy, bradycardia, pulmonary stenosis, atrial septal defect
and heterotaxy with suggestive linkage to
chromosome 6p. Hum Genet 122:595–603.
Whitsett JA, Tichelaar JW. 1999. Forkhead transcription factor HFH-4 and respiratory
epithelial cell differentiation. Am J Respir
Cell Mol Biol 21:153–154.
Yu X, Ng CP, Habacher H, Roy S. 2008. Foxj1
transcription factors are master regulators of
the motile ciliogenic program. Nat Genet
40:1445–1453.
317
Zariwala M, Noone PG, Sannuti A, Minnix S,
Zhou Z, Leigh MW, Hazucha M, Carson
JL, Knowles MR. 2001. Germline mutations in an intermediate chain dynein cause
primary ciliary dyskinesia. Am J Respir Cell
Mol Biol 25:577–583.
Zariwala MA, Leigh MW, Ceppa F, Kennedy MP,
Noone PG, Carson JL, Hazucha MJ, Lori A,
Horvath J, Olbrich H, Loges NT, Bridoux
AM, Pennarun G, Duriez B, Escudier E,
Mitchison HM, Chodhari R, Chung EM,
Morgan LC, de Iongh RU, Rutland J, Pradal
U, Omran H, Amselem S, Knowles MR.
2006. Mutations of DNAI1 in primary
ciliary dyskinesia: Evidence of founder effect
in a common mutation. Am J Respir Crit
Care Med 174:858–866.
Zariwala MA, Knowles MR, Omran H. 2007.
Genetic defects in ciliary structure and
function. Annu Rev Physiol 69:423–450.
Zhang M, Bolfing MF, Knowles HJ, Karnes H,
Hackett BP. 2004. Foxj1 regulates asymmetric gene expression during left-right axis
patterning in mice. Biochem Biophys Res
Commun 324:1413–1420.
Zhang Z, Alpert D, Francis R, Chatterjee B, Yu
Q, Tansey T, Sabol SL, Cui C, Bai Y,
Koriabine M, Yoshinaga Y, Cheng JF,
Chen F, Martin J, Schackwitz W, Gunn
TM, Kramer KL, De Jong PJ, Pennacchio
LA, Lo CW. 2009. Massively parallel
sequencing identifies the gene Megf8
with ENU-induced mutation causing
heterotaxy. Proc Natl Acad Sci USA 106:
3219–3224.
Zhu L, Belmont JW, Ware SM. 2006. Genetics of
human heterotaxias. Eur J Hum Genet 14:
17–25.
Zito I, Downes SM, Patel RJ, Cheetham ME,
Ebenezer ND, Jenkins SA, Bhattacharya
SS, Webster AR, Holder GE, Bird AC,
Bamiou DE, Hardcastle AJ. 2003. RPGR
mutation associated with retinitis pigmentosa, impaired hearing, and sinorespiratory
infections. J Med Genet 40:609–615.
Документ
Категория
Без категории
Просмотров
1
Размер файла
165 Кб
Теги
asymmetric, leftцright, disorder, heterotaxia, situ, inversus
1/--страниц
Пожаловаться на содержимое документа