Sex-dependent mechanisms for expansions and contractions of the CAG repeat on affected Huntington disease chromosomes

Journal Article · Tue Aug 01 04:00:00 EDT 1995 · American Journal of Human Genetics

OSTI ID:105242

Kremer, B; Theilmann, J; Spence, N ^[1]

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1. Univ. of British Columbia, Vancouver (Canada); and others

A total of 254 affected parent-child pairs with Huntington disease (HD) and 440 parent-child pairs with CAG size in the normal range were assessed to determine the nature and frequency of intergenerational CAG changes in the HD gene. Intergenerational CAG changes are extremely rare (3/440 [0.68%]) on normal chromosomes. In contrast, on HD chromosomes, changes in CAG size occur in {approximately}70% of meioses on HD chromosomes, with expansions accounting for 73% of these changes. These intergenerational CAG changes make a significant but minor contribution to changes in age at onset (r{sup 2}=.19). The size of the CAG repeat influenced larger intergenerational expansions (>7 CAG repeats), but the likelihood of smaller expansions or contractions was not influenced by CAG size. Large expansions (>7 CAG repeats) occur almost exclusively through paternal transmission (0.96%; P<10{sub -7}), while offspring of affected mothers are more likely to show no change (P=.01) or contractions in CAG size (P=.002). This study demonstrates that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene. Similar paternal sex effects are seen in the evolution of new mutations for HD from intermediate alleles and for large expansions on affected chromosomes. Affected mothers almost never transmit a significantly expanded CAG repeat, despite the fact that many have similar large-sized alleles, compared with affected fathers. The sex-dependent effects of major expansion and contractions of the CAG repeat in the HD gene implicate different effects of gametogenesis, in males versus females, on intergenerational CAG repeat stability. 22 refs., 4 figs., 3 tabs.

• OSTI ID: 105242
• Journal Information: American Journal of Human Genetics, Journal Name: American Journal of Human Genetics Journal Issue: 2 Vol. 57; ISSN AJHGAG; ISSN 0002-9297
• Country of Publication: United States
• Language: English

Related Subjects

55 BIOLOGY AND MEDICINE
BASIC STUDIES
ANIMAL CELLS
CHROMOSOMAL ABERRATIONS
GAMETOGENESIS
GENE MUTATIONS
GENES
HEREDITARY DISEASES
HUMAN CHROMOSOMES
MEIOSIS
NUCLEOTIDES
PATIENTS
POLYMERASE CHAIN REACTION
SEX DEPENDENCE
SIZE
STABILITY
STATISTICS