Polyglutamine Disorders
المؤلف:
Cohn, R. D., Scherer, S. W., & Hamosh, A.
المصدر:
Thompson & Thompson Genetics and Genomics in Medicine
الجزء والصفحة:
9th E, P127-128
2025-12-17
75
Several different neurologic diseases share the property that the protein encoded by the implicated gene has a variable-length string of consecutive glutamine residues, which can be encoded by the trinucleotide CAG. These so-called polyglutamine disorders result when an expansion of the CAG repeat leads to a protein with more glutamines than is compatible with normal function. Huntington disease (HD) is a well-known disorder that illustrates many of the common genetic features of such disorders. The neuropathology is dominated by degeneration of the striatum and the cortex. Individuals first present clinically in midlife, manifesting a characteristic phenotype of motor abnormalities (chorea, dystonia), personality changes, a gradual loss of cognition, and ultimately death.
For a long time, HD was thought to be a typical autosomal dominant condition with age-dependent penetrance. The disease is transmitted from generation to generation with a 50% risk to each offspring. Heterozygous and homozygous individuals carrying the abnormal allele have very similar phenotypes, although homozygotes may have a more rapid course of their disease. There are, however, obvious peculiarities that cannot be explained by simple autosomal dominant inheritance. First, the disease appears to develop at an earlier and earlier age in successive generations, a phenomenon referred to as anticipation. Second, anticipation seems to occur only when the pathogenic allele is transmitted by an affected father and not by an affected mother, a situation known as parental transmission bias.
The peculiarities of inheritance of HD are now readily explained by the discovery that the pathogenic allele is composed of an abnormally long CAG expansion in the coding region of the HTT gene. Normal individuals carry alleles with between 9 and 35 CAG repeats in their HTT gene, with the average being 18 or 19. Individuals affected with HD, however, have 36 or more repeats, with the average being around 46. Repeat numbers of 36 to 50 usually result in disease later in life, which explains the age-dependent penetrance that is a hallmark of this condition. A borderline repeat number of 36 to 39, although usually associated with HD, can be found in a few individuals who show no signs of the disease even at a fairly advanced age. The age of onset varies with how many CAG repeats are present (Fig. 1).
Fig1. Graph correlating approximate age of onset of Huntington disease with the number of CAG repeats found in the HTT gene. The solid line is the average age of onset, and the shaded area shows the range of age of onset for any given number of repeats. (Data courtesy Dr. M. Macdonald, Massachusetts General Hospital, Boston.)
How, then, does an individual come to have an expanded CAG repeat in his or her HTT gene? First, the person may have inherited it from a parent who has an allele expanded beyond the normal range but has not yet developed the disease. Second, the person may have inherited an expanded repeat from a parent with repeat length of 36 to 39 which may or may not cause disease in the parent’s lifetime but may have expanded on transmission, resulting in earlier-onset disease in later generations (i.e., anticipation). For example, in the pedigree shown in Fig. 2, individual I-1, now deceased, was diagnosed with HD at the age of 64 years; he was heterozygous for an expanded allele with 37 CAG repeats and a normal, stable allele with 25 repeats. Four of his children inherited the unstable allele, with CAG repeat lengths ranging from 42 to more than 100 repeats. Finally, unaffected individuals may carry alleles with repeat lengths at the upper limit of the normal range (29–35 CAG repeats) that can expand further during meiosis. CAG repeat alleles at the upper limits of normal that do not cause disease but are capable of expanding into the disease-causing range are known as intermediate alleles (previously premutations).
Fig2. Pedigree of family with Huntington disease. Shown beneath the pedigree is a Southern blot analysis for CAG repeat expansions in the HTT gene. In addition to a normal allele containing 25 CAG repeats, individual I-1 and his children, II-1, II-2, II-4, and II-5, are all heterozygous for expanded alleles, each containing a different number of CAG repeats. The repeat number is indicated below each individual. II-2, II-4, and II-5 are all affected; individual II-1 is unaffected at the age of 50 years but will develop the disease later in life. (Data courtesy Dr. Ben Roa, Baylor College of Medicine, Houston, Texas.)
Expansion in HTT alleles shows a paternal transmission bias and occurs most frequently during male gametogenesis; thus, the severe early-onset juvenile form of the disease, seen with the largest expansions (70–121 repeats), is always paternally inherited.
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