SCA8 CTG repeat : en masse contractions in sperm and intergenerational sequence changes may play a role in reduced penetrance

We recently described an untranslated CTG expansion that causes a previously undescribed form of spinocerebellar ataxia (SCA8). The SCA8 CTG repeat is preceded by a polymorphic but stable CTA tract, with the configuration (CTA)(1-21)(CTG)(n). The CTG portion of the repeat is elongated on pathogenic...

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Bibliographic Details
Published in:Human molecular genetics 2000-09, Vol.9 (14), p.2125-2130
Main Authors: MOSELEY, M. L, SCHUT, L. J, BIRD, T. D, KOOB, M. D, DAY, J. W, RANUM, L. P. W
Format: Article
Language:English
Subjects:
Alleles
Biological and medical sciences
Blotting, Southern
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
Family Health
Fathers
Female
Gene Duplication
Humans
Male
Medical sciences
Models, Genetic
Mothers
Nerve Tissue Proteins - biosynthesis
Nerve Tissue Proteins - genetics
Neurology
Pedigree
Penetrance
RNA, Long Noncoding
RNA, Untranslated
Sequence Analysis, DNA
Spermatozoa - metabolism
spinocerebellar ataxia
Spinocerebellar Ataxias - genetics
Trinucleotide Repeat Expansion
Trinucleotide Repeats - genetics
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Summary:We recently described an untranslated CTG expansion that causes a previously undescribed form of spinocerebellar ataxia (SCA8). The SCA8 CTG repeat is preceded by a polymorphic but stable CTA tract, with the configuration (CTA)(1-21)(CTG)(n). The CTG portion of the repeat is elongated on pathogenic alleles, which nearly always change in size when transmitted from generation to generation. To better understand the reduced penetrance and maternal penetrance bias associated with SCA8 we analyzed the sequence configurations and instability patterns of the CTG repeat in affected and unaffected family members. In contrast to other triplet repeat diseases, expanded alleles found in affected SCA8 individuals can have either a pure uninterrupted CTG repeat tract or an allele with one or more CCG, CTA, CTC, CCA or CTT interruptions. Surprisingly, we found six different sequence configurations of the CTG repeat on expanded alleles in a seven generation family. In two instances duplication of CCG interruptions occurred over a single generation and in other instances duplications that had occurred in different branches of the family could be inferred. We also evaluated SCA8 instability in sperm samples from individuals with expansions ranging in size from 80 to 800 repeats in blood. Surprisingly the SCA8 repeat tract in sperm underwent contractions, with nearly all of the resulting expanded alleles having repeat lengths of
ISSN:0964-6906
1460-2083
1460-2083
DOI:10.1093/hmg/9.14.2125