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Genetic considerations of gout.

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743
GENETIC CONSIDERATIONS OF GOUT
J. EDWIN SEEGMILLER
One of the greatest needs in medicine at the
present time is the identification of the precise genetic
factors that are responsible for some of the more common diseases. I t is known that a familial aggregation
exists for myocardial infarction, hypertension, diabetes
mellitus, manic depressive psychoses, schizophrenia,
chondrocalcinosis, and osteoarthritis as well as for
gout. Only within the past decade has a beginning
been made in identifying abnormal gene products responsible for gouty arthritis ( 1 4 ) and hypercholesterolemia (5). T h e approach being made in these
two disorders promises to provide examples for the
types of investigations that may prove fruitful for
other of the more common disorders.
T h e familial incidence found for gouty arthritis
within a given family depends to a considerable extent on the perseverance of the physician, as well as
on his ability to isolate environmental factors such as
lead poisoning which could be contributing to the
disease. A familial incidence has been reported by
some physicians in as many as 75y0 of families (2,3).
T h e clarity with which the inheritance of any given
disorder in a given pedigree can be recognized depends to a considerable extent on how close the abnormality being studied is to the abnormal gene
product. For example the inheritance of gouty arJ. Edwin Seegmiller, M.D.: Professor of Medicine, Department of Medicine, University of California, San Diego, La
Jolla, California
92093.
Address reprint requests to Dr. Seegmiller.
thritis is much less clear in a pedigree than is the
inheritance of hyperuricemia, because only 25y0 of
hyperuricemic relatives will have gouty arthritis (2,3).
In addition environmental factors can alter the degree
to which genetic factors are expressed. For example
liyperuricemia is a late manifestation of chronic lead
toxicity (6) and both Kelley and Klinenberg have reported a large number of gouty patients in certain
areas of the United States who showed evidence of
lead poisoning with a special EDTA infusion test
originated by Emmerson (6). I n some areas of the
country lead poisoning occurs from the high lead
content of “moonshine” whiskey.
T h e magnitude of knowledge of the human
genome in comparison to the amount yet to be
learned is very small, and knowledge of the genetic
factors operating in gout reflects this fact. T h e DNA
content of each human cell is sufficient to code lo7
polypeptide units, each containing an average of 150
amino acids (7). Estimates of the actual number of
genes present in the human species is only about 1 %
of this amount. A portion of the 99% of nongenetic
DNA is undoubtedly composed of reiterated sequences. T h e actual number of genes so far identified
as genetic factors in the human, as compiled by McKusick, is 1883, of which around half are firmly established (7). Therefore only about lo3 human genes
have been identified by their expression in humans.
Of these known genetic factors the abnormal gene
Arthritis and Rheumatism, Vol. 18, No. 6 (November-December 1975), Supplement
744
product has been identified i n only 150 to 200, and
most of these disorders are recessively inherited enzyme defects requiring homozygosity for clinical expression (8). Obviously we have just begun to understand some of tlie functions present in the human
genome.
T h e precise way in which a defective gene gives
rise to a clinically expressed hereditary disease has
been well worked out for only a relatively few abnormalities, most of which are recessively inherited
disorders. T h e greatest insight into the molecular
mechanism by which a mutation produces its effect
was provided by the detailed studies of sickle-cell
hemoglobin showing the substitution of just one of
the 146 amino acids i n the beta chain of hemoglobin
(9-1 1). T h e amino acid valine replaces the normal
glutamic acid to form sickle-cell hemoglobin (1 1).
As a result of the elucidation of tlie genetic code
by Nirenberg (12), the mutational event responsible
for the amino acid substitution can be traced to the
hypothetical substitution of a single base in tlie DNA
molecule resulting in uracil’s replacing the base adenine in messenger RNA. Of course we d o not yet have
the technical capability to analyze the messenger RNA
or tlie DNA to prove this presumed base substitution.
A base substitution in DNA can give rise to a
great many different types of defects in addition to
simple amino acid substitutions. Tlie chain terminating sequences UAG, UAA, or UGA can be formed
and thereby cause the ribosomes to stop translation
of tlie messenger RNA and thus interrupt the synthesis before completion of the polypeptide chain.
Another mechanism is tlie deletion or insertion of a
base that can form what is referred to as a “frameshift” mutation i n which the reading of three adjacent
bases by the ribosome is thrown off register by the
addition or deletion. Consequently the code for all
amino acids beyond tlie “frame-shift” mutation is
altered to produce incorporation of a n entirely different series of amino acids into the mutant protein.
“Frame-shift” mutations have so far been found only
in bacterial systems. Likewise mutations in an operator gene that cause enzyme deficiency or over-activity
have been found only in bacteria.
By far the majority of identified enzyme deficiencies show a recessive mode of inheritance. Therefore clinical expression is found only in the liomozygous state i n which the abnormal gene is contributed
from each heterozygous but clinically unaffected
parent. T h u s each offspring has a 25% chance of
SEEGMILLER
obtaining the two defective genes required for clinical
expression of the disorder.
Far less is known of the abnormal gene products responsible for dominantly inherited diseases. I n
these diseases clinical expression occurs in tlie heterozygous state; offspring of an affected parent therefore
have a 50% chance of being affected. An abnormality
of a structural protein is thought to underlie most
dominantly inherited disorders. T h e mutation described by Becker (pp 687-694) shows a dominantly
inherited increase in specific activity and is therefore
of special interest. Abnormalities of receptor sites or
cell transport mechanisms are also excellent candidates. Demonstration of a reduced number of receptor
sites for low-density lipoproteins on tlie surface of
fibroblasts cultured from patients with a dominantly
inherited hypercliolesterolemia has provided an excellent example of the mechanism by which a dominantly inherited disorder could be produced (5).
X-linked disorders are much more easily recognized from the pedigree because of their lack of maleto-male transmission. This recognition is based on tlie
presence of only one X chromosome in the male so
that all defects on that X chromosome can be expressed in the male. As a consequence 50% of the
male offspring of a female heterozygous for the disorder will be affected. Tests for heterozygosity are
based o n the presence of both phenotypically normal
and mutant cells i n hair roots or in fibroblasts cultured from skin biopsies. T h e two cell types confirm
tlie random inactivation of the X chromosome at an
early stage of fetal development (13,14). T h e influence
of the mutant cells is undoubtedly attenuated in the
female by partial correction of tlie defect in tlie mutant cells by metabolic cooperation (15).
A large gap in our knowledge exists between
those molecular mechanisms so far worked out in just
a few examples and tlie practical clinical problems
involving evaluation of a patient with gouty arthritis
with its hereditary tendency.
T h e pattern of inheritance can be especially
helpful in providing clues for detecting tlie rare gouty
patient with known aberrations of metabolism. For
example any gout patient whose family history shows
a maternal inheritance of the gout with no male-tomale transmission should be considered a possible
candidate for tlie variant of X-linked uric aciduria
(tlie Lesch-Nyhan syndrome), which is a n X-linked
disorder discussed in greater detail elsewhere (pp 673680). Another disorder with the same pattern of in-
GENETIC CONSIDERATIONS OF G O U T
745
heri tance is gout associated with vasopressin-unresponsive diabetes insipidus (16). T h e author and coworkers
have identified a few recessively inherited examples
of enzyme defects responsible for gout, but if there
is n o history of gout in the family and particularly
if the patient is a premenopausal woman with early
onset of gout, the possibility of the rare recessively inherited disorder, glycogen storage disease Type I,
should be considered. This disease is especially likely
if the patient gives a history of frequent epistaxis and
retardation of growth and sexual development, and
shows a liepatomegaly and a subnormal fasting blood
sugar level. If the patient proves to be intellectually
retarded instead of unusually intelligent, screening of
the urine for ketoacids should be made to look for
branched-chain ketoacids characteristic of maple syrup
urine disease. These are both very rare disorders, but
unless they are kept i n mind these specific types of
gout will certainly not be diagnosed.
If family history suggests a dominantly inherited disorder, the type of gout discussed by Becker
( p p 687-694) should be considered. It provides another
example of the mechanism by which a single gene
in heterozygous individuals can produce, in this case,
a metabolic overproduction of a normal end product.
T h e past decade has brought recognition of
the ubiquity of genetic heterogeneity. I n gouty arthritis this genetic heterogeneity occurs at many different
levels of organization. A wide variety of underlying
types of metabolic disorders are now known to produce the hyperuricemia required for development of
gouty arthritis. However genetic heterogeneity also
exists even within a single gene defect. All patients
with X-linked uric aciduria (the Lesch-Nyhan syndrome and its variants) show deficiency of the enzyme hypoxantliine-guanine phosphoribosyltransferase
(HPRT). A variety of degrees of severity of clinical
expression relate in part at least to the severity of the impairment of functional enzyme activity produced by
the mutation. T h e most severe deficiency and clinical
expression is of course the Lesch-Nyhan syndrome.
However even these patients show variations i n the
clinical expression of self-mutilation which may reflect, in part, genetic as well as environmental factors
(1-4,17). Less severe degrees of enzyme deficiency are
found in patients who develop only gouty arthritis,
whereas at values of enzyme activity between these extremes an attenuated neurologic involvement is found.
Even in patients with severe enzyme deficiency a
heterogeneity is found at the molecular level i n the
cause of the deficiency. A mutation affecting the
affinity of the enzyme for its substrate is found in
some patients, whereas in different gouty families an
increased or decreased thermal lability of the H P R T
enzyme has been found (I-4,17). As a consequence,
within the same family each patient generally tends
to show a similar degree of clinical expression.
Additional genetic factors conceivably can
modify the clinical expression even within the same
family. Amelioration or exacerbation of clinical presentation within a given family could reflect the presence of additional genetic mutations impinging upon
the mechanism involved in production of clinical expression of the disease.
Influence of Genetic Factors on Therapy
Long-term therapy of gouty arthritis is directed
toward correcting the hyperuricemia that is responsible for the development of the clinical disease. Because such therapy requires a lifelong commitment
to treatment with the drug, it is worth taking the
extra time and effort needed to prescribe the very
best drug for a particular patient’s form of disease.
To this end, the author has routinely determined the
amount of uric acid excreted in sequential 24-hour
collections of urine obtained during the last 3 days
of a 6-day period o n a purine-free diet. Immediately
after their presentation to the clinic with a n acute
attack of gout, most patients are well motivated to
undertake the extra effort required. Furthermore the
institution of long-term therapy with either a uricosuric drug o r allopurinol must await a defervescence
of the acute attack; this delay can be well used for
collecting data upon which the rationale of drug
selection can be based.
Most patients require very detailed instructions
on how to collect the 24-hour urine. Placing 3 ml of
toluene in the bottle and storing the urine at room
temperature will prevent development of microbial
contamination. Before a n aliquot is removed for
measurement of both uric acid and creatinine, any
urinary sediment must be brought into solution by
gentle warming in warm water with frequent agitation. T h e upper limit of normal for adult males is
600 mg of uric acid per day. Individuals excreting
less than this amount who have normal renal function are obviously not flagrant overproducers of uric
acid. Presumably their primary cause of hyperuricemia
is a less efficient renal mechanism for excretion of uric
acid than is found in normal subjects. T h e uricosuric
SEEGMILLER
746
drug probenecid provides the most appropriate rational treatment because it enhances the effectiveness
of renal clearance of uric acid by the kidney. Excretion of quantities of uric acid greater than 600 mg
per day is evidence of substantial overproduction of
uric acid. This group of patients should be given allopurinol for treatment because it not only blocks uric
acid formation but decreases the total amount of purines being formed and thereby has a special corrective therapeutic effect. Exceptions to this generalization are patients with X-linked uric aciduria who
merely substitute the oxypurine precursors of hypoxanthine and xanthine for the deficit in uric acid production. Evidently HPRT enzyme is required for this
additional effect of allopurinol. Nevertheless these patients d o benefit from the capability of allopurinol to
divide the load of a sparingly soluble metabolite, uric
acid, into three different molecular species, each with
its own independent solubility. Furthermore hypoxanthine and xanthine are excreted much more efficiently
by the kidney than is uric acid.
SUMMARY
A great many genetic factors and genetic meclianisms are involved in the production of gouty arthritis. Genetic heterogeneity is to be expected in this
disorder at all levels of expression. T h e genetic factors
responsible for hyperuricemia, whether from gross
overproduction of uric acid or from decreased renal
excretion, can influence such practical matters as the
selection of the proper therapy for control of the
disease.
REFERENCES
1. Seegmiller JE: Biochemical and genetic studies of an
X-linked neurological disease. Harvey Lectures, Series
65, New York, Academic Press, 1971, pp 175-192
2. Seegmiller JE: Diseases of purine and pyrimidine
metabolism, Duncan’s Diseases of h4etabolism. Seventh
Edition. Edited by PK Bondy, LE Rosenberg. Philadelphia, W. B. Saunders Company, 1974, pp 655-774
3. Wyngaarden JB, Kelley WN: Gout, T h e Metabolic
Basis of Inherited Disease. Third Edition. Edited by
JB Stanbury, JB Wyngaarden, DS Fredrickson. New
York, hlcGraw-Hill Book Company, 1972, pp 889-968
4. Kelley IYN, Wyngaarden JB: T h e Lesch-Nyhan syndrome, T h e hletabolic Basis of Inherited Disease. Third
Edition. Edited by JB Stanbury, JB M7yngaarden, DS
Fredrickson. New York, hIcGraw-Hill Book Company,
1972, pp 969-991
5. Golditein JL, Brown hIS: Binding and degradation of
low density lipoproteins by cultured human fibroblasts.
Comparison of cells from a normal subject and from a
patient with homozygous familial hypercholesterolemia.
J Biol Chem 249:5153-5162, 1973
6. Emmerson BT: Chronic lead nephropathy: the diagnostic use of calcium EDTA and the association with
gout. Aust Ann hIed 12:310, 1963
7. McKusick V: Mendelian Inheritance in hlan. Catalogs
of Autosomal, Dominant, Autosomal Recessive, and XLinked Phenotypes. Third Edition. Baltimore, T h e
Johns Hopkins Press, 1971
8. Raivio KO, Seegmiller JE: Genetic diseases of metabolism. Annu Rev Biochem 41:543-576, 1972
9. Pauling L, Itano HA, Singer SJ, et al: Sickle cell
anemia: a molecular disease. Science 110:543, 1949
10. Pauling L: Abnormality of Hemoglobin Molecules in
Hereditary Hemolytic Anemias. Harvey Lectures, New
York, Academic Press, 1954
1 I . Ingram VM: Hemoglobin and Its Abnormalities. Spring
field, Charles C. Thomas, 1961
12. Nirenberg MW, hlatthaei KH: T h e dependence of
cell-free protein synthesis in E . colz upon naturally occurring or synthetic polyribonucleotides. Proc Natl Acad
Sci USA 47: 1588, 1961
13. Lyon hIF: Gene action in the X-chromosome of the
Nature 190:372-373, 1961
mouse (Mus. musculus L),
14. Beutler E: Biochemical abnormalities associated with
hemolytic states, Mechanisms of Anemia. Edited by IM
Weinstein, E Beutler. New York, McGraw-Hill Book
Company, 1962, pp 195-236
15. Friedmann T, Seegmiller JE, Subak-Sharpe JH: Metabolic cooperation between genetically marked human
fibroblasts in tissue culture. Nature (Lond) 220:272274, 1968
16. Gorden P, Robertson GL, Seegmiller JE: Hyperuricemia: a concomitant of congenital vasopressinresistant diabetes insipidus in the adult. N Engl J bled
284:1057-1060, 1971
17. Seegmiller JE: Inherited deficiency of hypoxanthineguanine phosphoribosyltransferase in X-linked aciduria.
Am Hum Genet 6:75-163, 1976
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