Vol. 10: Winter, 1994
Nontraditional Inheritance
Triplet Repeat Disorders
Progression in severity of a disorder as it is passed down through generations is called anticipation. The term is also used to describe disorders in which the age of onset becomes progressively younger with each new generation. Reports of apparent anticipation have been common but, until recently, were most often ascribed to ascertainment bias or additive effects of multiple genes. Although anticipation may appear to have occurred in patients who have inherited germline mutations from more mildly affected mosaic parents, the term is now being primarily applied to disorders involving the newly discovered phenomenon of expansion of nucleotide triplet repeats.
Expansions of repeated DNA sequences represent a newly discovered type of human mutation. Such mutations and their phenotypic consequences occur when many extra copies are made of three basepair DNA sequences normally found in low copy number in or near genes. The breakthrough in this area came with the discovery that the mutation responsible for the fragile X mental retardation syndrome involves multiple replications of the nucleotide repeat cytosine-guanine-guanine (CGG) normally present in copy numbers of up to 50 in the promoter region of the FMR I (Fragile X Mental Retardation 1) gene that is inactivated in affected boys. In affected individuals, as many as 1,000 copies of CGG repeats may be encountered.
This expansion of triple nucleotide repeats has no precedent in experimental animals but was quickly shown to cause four other human disorders with unusual inheritance patterns. The first, spinobulbar muscular atrophy (Kennedy Disease) is a rare X-linked disorder in which the mutation involves expansion of a cytosine-adenosine-guanine (CAG) repeat. A second, more common, disorder called myotonic dystrophy results from expansion involving excessive copying of CTG repeat. Huntington disease, also autosomal dominant, was found to result from expansion of a triplet repeat (CAG) as well. The most recent addition to the growing list of disorders caused by expansion of triplet repeats is spinocerebellar ataxia type 1 which appears to be the result of expansion of a CAG repeat in the transcribed region of a previously unidentified gene on chromosome 6.
How frequently this kind of mutation occurs in the human genome is not clear. Families with psychiatric disorders such as bipolar affective disorder are now being analyzed for evidence of anticipation. At least one other example of an expanding repeat has been found using a new and ingenious version of the polymerase chain reaction (ligase-PCR), but the family reported has no apparent disease.
Anticipation occurs in all five of the clinical disorders in which triplet expansion is found, indicating that these sequences are not stable. There is general correlation between the size of the expansion (i.e. the number of repeated triplets) and the severity of the phenotype. However, it is important to point out that expansion and anticipation do not explain all phenotypic variability of the disorders in which they occur.
- Fragile X
Anticipation was not initially recognized in fragile X syndrome. Inheritance of this X-linked disorder was unusual, however, in that a mutation of some kind could clearly be passed on by unaffected transmitting males, but only became expressed after being passed through a female.
When the mutation present in affected individuals was found to involve multiple copies of a CGG triplet repeat, it also became possible to track repeat size through families. Transmitting males were found to carry what was called a "premutation" of repeated CGG sequences with copy numbers greater than 50 but less than 200.
Daughters of transmitting males were not found to be affected; they carried premutations only. However, their sons who inherited the mutant X chromosome usually were affected as were daughters who also got the mutant X. Apparently, upon passage through a carrier female, premutations more often than not are expanded to copy numbers exceeding 200. Thus, females may pass on both premutations and fully expanded mutations. Fully expanded mutations of greater than 200 copies are not found in sperm, so males transmit only premutations.
Although expansion to full mutations in fragile X syndrome had been assumed to occur during maternal meiosis, recent investigations indicate that the expansion is probably occurring early in embryogenesis and occasionally leads to mosaicism. The fragile X syndrome is further complicated by the fact that fully expanded mutations are also modified by methylation. Abnormal phenotypes are associated with decreased expression of the FMR- I gene product which appears to result from the combined effects of both expansion and methylation.
- Myotonic Dystrophy
The story of anticipation in myotonic dystrophy reveals even more that is unusual about the inheritance of unstable triplet nucleotide repeats in humans. This autosomal dominant disorder is now known to result from altered expression of a gene for a protein kinase enzyme (myotonin kinase) located on chromosome 19.
The disorder is characterized by progressive weakness, cataracts and cardiomyopathy. It presents most often in adults but as it is passed on through generations it affects offspring at younger ages. This apparent anticipation had been previously dismissed as ascertainment bias, but it was clear that something unusual was happening because severe, congenital symptoms occasionally occurred in offspring of even mildly affected mothers, but not similarly affected fathers.
Molecular analyses of the myotonin gene now reveal that expansion of multiple copies of a CTG repeat located in the 3' non-coding region of the gene causes myotonic dystrophy. The mechanism appears to involve overproduction of myotonin kinase. As in fragile X syndrome, premutations play a role. Normally, between 5 and 35 copies of the repeat are present. Expansion to 50 to 80 copies constitutes a premutation that is unstable and expands in subsequent generations. Unlike the fragile X mutation, however, the myotonic dystrophy premutation expands when passed through both males and females, although expansion through females is often much greater than through males. Affected individuals have copy numbers greater than 80 with up to several thousand copies found in severely congenitally affected patients.
In most families with myotonic dystrophy, anticipation of symptoms correlates well with the number of repeated triplet copies measured in white blood cells. However, this correlation is poor in some individuals, suggesting involvement of additional factors. The suggestion that expansion of the fragile X mutation occurs during embryogenesis implies that mosaicism for expansion size could also play a role in myotonic dystrophy. For this reason, presymptomatic testing in this disorder (i.e. predicting the age of onset and severity of symptoms by measuring the size of the triplet repeat expansions in white blood cells) should be approached with caution.
So far, expansion to greater than approximately 900 repeats has correlated consistently enough with early onset disease to be used in prenatal diagnosis of myotonic dystrophy. The reason this marked an expansion occurs when the mutation is passed through mothers is not understood. Imprinting would seem an important consideration, but no evidence supporting a role for methylation in this disorder has yet been presented. Decreases in copy number have also been occasionally reported across generations in both myotonic dystrophy and, less frequently, in fragile X syndrome, but most pedigrees reflect progressive expansion.
- Huntington Disease
In contrast to what is seen in fragile X syndrome and myotonic dystrophy, triplet repeats expand to less than 200 copy numbers in individuals, even children and adolescents, affected with Huntington chorea. Moreover, there is no easily identifiable premutation in this disorder. Unaffected people usually have repeat copy numbers less than 30 and affected patients generally have copy numbers greater than 40. Both unaffected and affected persons are found among the population carrying 30 to 40 repeats.
Molecular studies of the inheritance of this disorder have been hampered by its late onset. There are few families from whom DNA is available in multiple generations. In addition, the clinical diagnosis is difficult and misdiagnosed patients may have been included among "affected" groups.
Expansion at the Huntington chorea locus has been documented in sperm cells and is more likely to occur when the mutation passes through males. This is in contrast to fragile X syndrome, where expansion appears to occur after fertilization, and to both fragile X and myotonic dystrophy, where it is the maternally inherited mutation that undergoes the greatest expansion.
These findings strongly suggest that there may be multiple mechanisms for expansion of triplet repeats in humans. There is also a suggestion of selection against large expansion in sperm. No direct evidence of an expansion mechanism has yet been presented, but most molecular geneticists suggest that problems arise during DNA replication. The most popular theories hypothesize "stuttering" mechanisms involving attachment and reattachment of replication enzymes in regions of repeated triplets.
How many more surprises await investigators studying the, so far, uniquely human phenomenon of expanding triplet repeats remains to be seen.
The Genetic Drift Newsletter is not copyrighted. Readers are free to duplicate all or parts of its contents. The Genetic Drift Newsletter is published semiannually by the Mountain States Regional Genetic Services Network for associates & those interested in Human Genetics. In accordance with accepted publication standards, we request acknowledgement in print of any article reproduced in another publication. The views expressed in the newsletter do not necessarily reflect local, state, or federal policy. For additional information, contact Carol Clericuzio, M.D., Editor, Department of Pediatrics, The University of New Mexico, Albuquerque, NM, 87131
Nontraditional Inheritance: Table of Contents
Mosaicism
Mitochondrial Inheritance
Uniparental Disomy and Genomic Imprinting
Triplet Repeat Disorders
Additional Reading
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