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An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family.

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An LRRK2 Mutation as a
Cause for the Parkinsonism
in the Original PARK8
Manabu Funayama, PhD,1 Kazuko Hasegawa, MD, PhD,2
Etsuro Ohta, MMSci,1 Noriko Kawashima, MD,3
Masaru Komiyama, BS,1 Hisayuki Kowa, MD, PhD,4
Shoji Tsuji, MD, PhD,5 and Fumiya Obata, PhD1
We detected a missense mutation in the kinase domain of
the LRRK2 gene in members with autosomal dominant
Parkinson’s disease of the Japanese family (the Sagamihara family) who served as the basis for the original defining of the PARK8 Parkinson’s disease locus. The results of the Sagamihara family, in combination with the
unique pathological features characterized by pure nigral
degeneration without Lewy bodies, provided us with
valuable information for elucidating the protein structure–pathogenesis relationship for the gene product of
LRRK2. We did not detect this mutation or other known
mutations of the LRRK2 gene in Japanese patients with
sporadic Parkinson’s disease.
Ann Neurol 2005;57:918 –921
Parkinson’s disease (PD) [MIM 168600] is one of the
most common neurological disorders and is characterized by rigidity, bradykinesia, tremor, and postural instability. Although PD is a sporadic disease in most
cases, various hereditary forms presenting clinical phenotypes similar to those of sporadic PD have been recognized. Molecular genetic studies on these familial forms
of parkinsonism have substantially advanced our understanding of the molecular pathogenesis of this disease.1– 6
In a previous study, we identified a new locus for
PD, PARK8 (12p11.2-q13.1), by genome-wide linkage
From the 1Division of Clinical Immunology, Kitasato University
Graduate School of Medical Sciences; 2Department of Neurology,
National Hospital Organization, Sagamihara National Hospital,
Sagamihara; 3Kawashima Neurological Clinic, Fujisawa; 4Kitasato
University, Sagamihara; and 5Department of Neurology, Tokyo
University, Tokyo, Japan.
Received Dec 27, 2004, and in revised form Mar 11, 2005. Accepted for publication Mar 11, 2005.
Current address for Dr Funayama: Research Institute for Diseases of
Old Ages, School of Medicine, Juntendo University, Tokyo, Japan.
Published online May 4, 2005 in Wiley InterScience
( DOI: 10.1002/ana.20484
Address correspondence to Dr Obata, Department of Immunology,
Kitasato University School of Allied Health Sciences, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555, Japan.
© 2005 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
analysis of one large Japanese family with autosomal
dominant PD (the Sagamihara family).7 Subsequently,
PARK8 has been confirmed as the PD locus in several
white families.8 Recently, a gene named LRRK2
(leucine-rich repeat kinase 2) was reported to be the
gene responsible for PARK8-linked PD.9,10 Five individual missense mutations at four positions were detected in several white families. Because the PARK8 PD
locus was originally defined for the Sagamihara family,
it is crucial to examine whether LRRK2 is the gene responsible for the disease in this family. In addition,
analysis of the Sagamihara family is essential because of
the unique pathological characteristics of their disease,
pure nigral degeneration without Lewy bodies,7,11,12
which are in marked contrast to those reported in the
PARK8-linked white families.
Subjects and Methods
Subjects and Genomic DNA
Details of the clinical and pathological features of the original patients in the Sagamihara family have been published
previously.7,11,12 Genomic DNA samples from the 25 members of the Sagamihara family and its related family (19 patients, 5 unaffected members, and 1 spouse), 188 patients
with sporadic PD, and 184 healthy volunteers were used for
this study after obtaining informed consent from all subjects.
This study was approved by the ethics committee of the National Hospital Organization, Sagamihara National Hospital.
Sequencing of the LRRK2 Exons
The 51 exons of the LRRK2 gene were amplified from
genomic DNA using polymerase chain reaction primers,
some of which were made from the report by Paisán-RuıÅLz
and colleagues,9 and the amplified DNA fragments were subjected to direct nucleotide sequence analysis using a BigDye
Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems,
Foster City, CA).
Analysis of LRRK2 Mutations in Patients with
Sporadic Parkinson’s Disease and Healthy Volunteers
The mutations of the LRRK2 gene, 3342A典G (exon 24),
3364A典G (exon 25), and 5096A典G (exon 35), were examined by direct nucleotide sequence analysis of the polymerase
chain reaction–amplified fragments of each exon. The mutations 4321C典T or G (exon 31) and 6059T典C (exon 41) were
examined by digestion of the polymerase chain reaction–amplified fragments of each exon with Bsh1236I (Fermentas,
Hanover, MD) and Bts1 (New England Biolabs, Beverly,
MA), respectively.
Analysis of the LRRK2 Gene in the Sagamihara
We detected a heterozygous mutation of I2020T
(6059T典C) in exon 41 of the LRRK2 gene in all 19
affected members of the Sagamihara family (Figs 1 and
2). We further analyzed another small pedigree that has
been suggested to share a haplotype identical with that
of the Sagamihara family and detected the I2020T mutation in the two affected individuals of this pedigree.
Although this mutation was also carried by three unaffected individuals who were older than the mean age at
onset in the Sagamihara family (54 years), their ages of
73, 58, and 56 years are within the variation of age at
onset in this family (range, 39 –76 years). This mutation was not detected in 368 chromosomes derived
Fig 1. Mutation of the LRRK2 gene. Mutations reported in white families (top) and that detected in the Sagamihara family (bottom) are shown. The nucleotide and amino acid change, as well as the sequences of other species, are shown in the bottom part of
the figure. The National Center for Biotechnology Information/GenBank accession numbers are AY792511 for human, AAH34074
for mouse, XP_235581 for rat, XP_425418 for chicken, and AAH76853 for Xenopus.
Funayama et al: LRRK2 of the Original PARK8 Family
Fig 2. Pedigree of the Sagamihara family (top) and its related family (bottom left). Individuals younger than the mean age at onset
(54 years) are not included in the pedigree. The sexes are disguised to safeguard the confidentiality of the family members. M ⫽
mutation; W ⫽ wild type.
from unrelated healthy Japanese volunteers, making the
pathogenic nature of this mutation highly likely. We
did not find any disease-specific mutation in the other
50 exons, and all the other base substitutions turned
out to be polymorphisms. Furthermore, currently, we
have analyzed 125 other genes (1,064 exons) in the
PARK8 candidate region and have not detected any
other disease-specific mutations except for the I2020T
mutation of LRRK2. We therefore conclude that
LRRK2 is the gene responsible for PARK8 PD.
Analysis of the LRRK2 Gene in Japanese Patients
with Sporadic Parkinson’s Disease
Next, we examined whether the I2020T mutation is
detectable in Japanese patients with sporadic PD in the
general population. None of the 188 Japanese PD patients had the mutation. We further examined the
same patients with sporadic PD for five other mutations that have been reported in white families (ie,
L1114L [3342A典G, exon 24], I1122V [3364A典G, exon
25], R1441C or G [4321C典T or G, exon 31], and
Y1699C [5096A典G, exon 35])9,10 and found that none
of the patients had any of these mutations.
The amino acid I2020 is located in the kinase-motif
domain of LRRK2 and is conserved among various species, suggesting that the mutation at this position
causes considerable functional changes in the gene
product, although its precise function remains unknown (see Fig 1). The I2020T mutation detected in
the Sagamihara family is identical to that detected in
Family 32 who Zimprich and colleagues10 reported.
Thus, two independent PD families apparently have
the common mutation, further supporting the conclusion that this mutation is essential for the pathogenesis
of PARK8-related PD. The typical clinical features of
Annals of Neurology
Vol 57
No 6
June 2005
PD in the affected members of the Sagamihara family
are similar to those reported for Family 32 but distinct
from those of patients of Family A with the other mutation, Y1699C, some of whom were reported to exhibit dementia.10 The mean age at onset for patients
with the I2020T mutation was 54 years, in both the
Sagamihara family and Family 32; the mean age at onset for patients with the R1441C or R1441G mutation
was 65 years in both the Basque family and Family
D.9,10 Thus, the positions of these mutations appear to
correlate with the age at onset. The mean ages at onset
for other mutations, although they were obtained from
single or small families, were 73 (3342A⬎G), 51
(I1122V), and 53 or 65 (Y1699C) years.9,10
The pathological features of the disease in the affected
members of the Sagamihara family were pure and mild
nigral degeneration with neither Lewy bodies nor neurofibrillary tangles. Although those members of Family
32 having the identical mutation of I2020T were not
described, the pathological features seen in affected
members of the Sagamihara family are distinct from
those of patients with mutations at other positions of
LRRK2. These results suggest the possibility that the
pathogenetic mechanisms caused by mutations of
LRRK2 are diverse in relation to nigral neuronal degeneration and Lewy body formation, depending on the
forms of the mutations. Thus, the results obtained from
the Sagamihara family have provided us with valuable
information for elucidating the protein structure–pathogenesis–symptom relationship for the gene product of
It has been reported that the R1441C and Y1699C
mutations are not detectable in white patients with sporadic PD, although the R1446G mutation has been detected in some Basque patients. In Japanese patients
with sporadic PD from among the general population,
we detected none of these mutations; we also did not
detect the additionally analyzed mutations 3342A⬎G,
I1122V, and I2020T, the latter being the mutation
found in the Sagamihara family. Our results indicate
that these LRRK2 mutations are not a direct genetic risk
factor for sporadic PD in the Japanese population. It is
possible, however, that the gene product of LRRK2 plays
a key role, either causal or protective, in the pathogenesis
of sporadic PD in combination with other genetic or
environmental factors.
This study was supported by the Japanese Ministry of Education,
Culture, Sports, Science and Technology (Grant-in-Aid for Scientific Research 16015298 and 16590843, K.H.) and Kitasato University School of Allied Health Sciences (Grant-in-Aid for Research
Project 2004-01, F.O.).
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the alpha-synuclein gene identified in families with Parkinson’s
disease. Science 1997;276:2045–2047.
2. Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin
gene cause autosomal recessive juvenile parkinsonism. Nature
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4. Leroy E, Boyer R, Auburger G, et al. The ubiquitin pathway in
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Science 2004;304:1158 –1160.
7. Funayama M, Hasegawa K, Kowa H, et al. A new locus for
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8. Zimprich A, Muller-Myhsok B, Farrer M, et al. The PARK8
locus in autosomal dominant parkinsonism: confirmation of
linkage and further delineation of the disease-containing interval. Am J Hum Genet 2004;74:11–19. Erratum in Am J Hum
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9. Paisán-RuıÅLz C, Jain S, Evans EW, et al. Cloning of the gene
containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 2004;44:595– 600.
10. Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2
cause autosomal-dominant Parkinsonism with pleomorphic pathology. Neuron 2004;44:601– 607.
11. Hasegawa K, Kowa H. Autosomal dominant familial Parkinson
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POLG Mutations and Alpers
Guido Davidzon, MD,1 Michelangelo Mancuso, MD,1,2
Silvio Ferraris, MD,1 Catarina Quinzii, MD,1
Michio Hirano, MD,1 Heidi L. Peters, MD,3
Denise Kirby, PhD,3 David R. Thorburn, PhD,3
and Salvatore DiMauro, MD1
Alpers–Huttenlocher syndrome (AHS) an autosomal recessive hepatocerebral syndrome of early onset, has been
associated with mitochondrial DNA (mtDNA) depletion
and mutations in polymerase gamma gene (POLG). We
have identified POLG mutations in four patients with
hepatocerebral syndrome and mtDNA depletion in liver,
who fulfilled criteria for AHS. All were compound heterozygous for the G848S and W748S mutations, previously reported in patients with progressive external ophtalmoplegia or ataxia. We conclude that AHS should be
included in the clinical spectrum of mtDNA depletion
and is often associated with POLG mutations, which can
cause either multiple mtDNA deletions or mtDNA depletion.
Ann Neurol 2005;57:921–924
Alpers–Huttenlocher syndrome (AHS; progressive infantile poliodystrophy) is an autosomal recessive hepatocerebral syndrome. The typical course of AHS includes severe developmental delay, intractable seizures,
liver failure, and death in childhood.1,2 Refractory seizures, cortical blindness, progressive liver dysfunction,
and acute liver failure after exposure to valproic acid
are considered diagnostic features.3,4 The neuropathological hallmarks of AHS are neuronal loss, spongiform
degeneration, and astrocytosis of the visual cortex.
Liver biopsy results show steatosis, often progressing to
Morphological and biochemical studies had suggested involvement of the mitochondrial respiratory
chain in AHS.6 – 8 A point mutation in the mtDNA
gene-encoding subunit II of cytochrome c oxidase
From the 1Department of Neurology, Columbia University College
of Physicians and Surgeons, New York, NY; 2Department of Neurosciences, Neurological Institute, University of Pisa, Pisa, Italy;
Murdoch Childrens Research Institute and Genetic Health Services, Victoria Royal Children’s Hospital; and Department of Paediatrics, University of Melbourne, Melbourne, Australia.
Received Sep 8, 2004, and in revised form Mar 2, 2005. Accepted
for publication Mar 13, 2005.
Published online May 23, 2005, in Wiley InterScience
( DOI: 10.1002/ana.20498
Address correspondence to Dr DiMauro, 4-420 College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032.
© 2005 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
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