De Novo Expansion of Intermediate Alleles in Spinocerebellar Ataxia 7 (original) (raw)
Related papers
Spinocerebellar ataxia 17: full phenotype in a 41 CAG/CAA repeats carrier
Cerebellum & ataxias, 2018
Spinocerebellar ataxia 17 (SCA17) is one of the most heterogeneous forms of autosomal dominant cerebellar ataxias with a large clinical spectrum which can mimic other movement disorders such as Huntington disease (HD), dystonia and parkinsonism. SCA17 is caused by an expansion of CAG/CAA repeat in the Tata binding protein () gene. Normal alleles contain 25 to 40 CAG/CAA repeats, alleles with 50 or greater CAG/CAA repeats are pathological with full penetrance. Alleles with 43 to 49 CAG/CAA repeats were also reported and their penetrance is estimated between 50 and 80%. Recently few symptomatic individuals having 41 and 42 repeats were reported but it is still unclear whether CAG/CAA repeats of 41 or 42 are low penetrance disease-causing alleles. Thus, phenotypic variability like the disease course in subject with SCA17 locus restricted expansions remains to be fully understood. The patients was a 63-year-old woman who, at 54 years, showed personality changes and increased frequency o...
European Journal of Human Genetics, 1999
Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disease characterised by the association of cerebellar ataxia and, in most patients, progressive macular degeneration leading to loss of autonomy and blindness. The patients die after 5-30 years of evolution. The cause of the disease has been identified as a (CAG) n repeat expansion in the coding sequence of the SCA7 gene on chromosome 3p. De novo mutations occur on intermediate-sized alleles carrying from 28 to 35 CAG repeats. Neomutations explain the persistence of the disease in spite of the great instability of the repeat sequence which results in the appearance of juvenile onset patients and the extinction of the disease within families. This rare disorder has been reported in a wide variety of countries and ethnic groups. In a large number of SCA7 families (n = 41) of different origins, we have determined the haplotypes segregating with the mutation of several microsatellite markers close to the SCA7 gene and of a new intragenic polymorphism (G 3145 TG/A 3145 TG). Four different haplotypes were found for centromeric markers (G 3145 TG/A 3145 TG-D3S1287-D3S3635) in the majority of the kindreds from four different geographic regions: A-2-4 in Korea; A-3-6 in North Africa, B-3-6 in continental Europe and A-4-6 in the UK and USA. The haplotypes in the Jamaican, Filipino, Brazilian and German families were different, suggesting that independent regional founders are at the origin of the SCA7 mutation in each population. Two different haplotypes were observed, however, in two families from the same rural area in central Italy in which de novo SCA7 mutations on intermediate alleles have been observed, suggesting the existence of different pools of at-risk chromosomes in this population.
Journal of Human Genetics, 2005
Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant cerebellar ataxia caused by CAG repeat expansion. We found expansion at SCA7 locus in only two out of 235 Indian families clinically diagnosed for ataxia. In one of the families, a de novo mutation was observed wherein a paternal allele in intermediate range of 31 CAG repeats expanded to 59 in the offspring leading to the disease. No expanded alleles were observed in the sperm of the transmitting parent by small pool PCR. This suggests that de novo expansion by a pre-zygotic event is unlikely and could be post-zygotic. SCA7 expanded alleles from the two families were present on different genetic backgrounds, indicating multiple origins of the mutation.
Cerebellum & Ataxias
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder that primarily affects the cerebellum and brainstem. The genetic mutation is an expansion of CAG trinucleotide repeats within the coding region of the ataxin-1 gene, characterizing SCA1 as a polyglutamine expansion disease like Huntington's. As with most polyglutamine expansion diseases, SCA1 follows the rules of genetic anticipation: the larger the expansion, the earlier and more rapid the symptoms. Unlike the majority of polyglutamine expansion diseases, the presence of histidine interruptions within the polyglutamine tract of ataxin-1 protein can prevent or mitigate disease. The present review aims to synthesize three decades of research on the ataxin-1 polyglutamine expansion mutation that causes SCA1. Data from genetic population studies and case studies is gathered along with data from manipulation studies in animal models. Specifically, we examine the molecular mechanisms that cause tract expansions and contractions, the molecular pathways that confer instability of tract length in gametic and somatic cells resulting in gametic and somatic mosaicism, the influence of maternal or paternal factors in inheritance of the expanded allele, and the effects of CAT/histidine interruptions to the ataxin-1 allele and protein product. Our review of existing data supports the following conclusions. First, polyCAG expansion of gametic alleles occur due to the failure of gap repair mechanisms for single or double strand breaks during the transition from an immature haploid spermatid to a mature haploid sperm cell. Equivalent failures were not detected in female gametic cells. Second, polyCAG expansion of somatic alleles occur due to hairpins formed on Okazaki fragments and slipped strand structures due to failures in mismatch repair and transcription-coupled nucleotide excision repair mechanisms. Third, CAT trinucleotide interruptions, which code for histidines in the translated protein, attenuate the formation of slipped strand structures which may protect the allele from the occurrence of large expansions. Many of the mechanisms of expansion identified in this review differ from those noted in Huntington's disease indicating that gene -or sequencespecific factors may affect the behavior of the polyCAG/glutamine tract. Therefore, synthesis and review of research from the SCA1 field is valuable for future clinical and diagnostic work in the treatment and prevention of SCA1.
Comparative studies of the CAG repeats in the spinocerebellar ataxia type 1 (SCA1) gene
American Journal of Medical Genetics, 1997
The CAG repeat tract at the autosomal dominant spinocerebellar ataxia type 1 (SCA1) locus was analyzed in SCA1 families and French-Acadian, African-American, Caucasian, Greenland Inuit, and Thai populations. The normal alleles had 9-37 repeats, whereas disease alleles contained 44-64 repeats. The CAG repeat tract contained one or two CAT interruptions in 44 of 47 normal human chromosomes and in all five chimpanzees examined. In contrast, no CAT interruptions were found in Old World monkeys or expanded human alleles. The number and positions of CAT interruptions may be important in stabilizing CAG repeat tracts in normal chromosomes. At least five codons occupy the region corresponding to the polyglutamine tract at the SCA1 locus in mice, rats, and other rodents. They comprise three or four CCN (coding for proline) in addition to one or two CAG repeats. Am.
Molecular features of the CAG repeats of spinocerebellar ataxia 6 (SCA6)
Human Molecular Genetics, 1997
Spinocerebellar ataxia 6 (SCAO) is an autosomal dominant spinocerebellar degeneration caused by the expansion of the polymorphic CAG repeat in the human alA voltage-dependent calcium channel subunit gene (CACNLlA4 gene). We have analyzed 60 SCA6 individuals from 39 independent SCAO Japanese families and found that the CAG repeat length is inversely correlated with the age of onset (n = 58, r={.51, P< 0.0001). SCA6 chromosomes contained 21-30 repeat units, whereas normal chromosomes displayed f17 repeats. There was no overlap between the normal and affected CAG repeat number. The anticipation of the disease was observed clinically in all eight parent-child pairs that we examined; the mean age of onset was significantly lower (P = 0.0042) in chiiciren than in parents. However, a parent+hiici analysis showed the increase in the expansion of CAG repeals only in one pair and no diminution in any affected cases. This result suggests that factors other than CAG repeats may produce the clinicalanticipation. A homozygotic case could not demonstrate an unequivocal gene dosage effect on the age of onset.
Human Genetics, 2000
To identify various subtypes of spinocerebellar ataxias (SCAs) among 57 unrelated individuals clinically diagnosed as ataxia patients we analysed the SCA1, SCA2, SCA3, SCA6, SCA7 and DRPLA loci for expansion of CAG repeats. We detected CAG repeat expansion in 6 patients (10.5%) at the SCA1 locus. Ten of the 57 patients (17.5%) had CAG repeat expansion at the SCA2 locus, while four had CAG expansion at the SCA3/MJD locus (7%). At the SCA6 locus there was a single patient (1.8%) with 21 CAG repeats. We have not detected any patient with expansion in the SCA7 and DRPLA loci. To test whether the frequencies of the large normal alleles in SCA1, SCA2 and SCA6 loci can reflect some light on prevalence of the subtypes of SCAs we studied the CAG repeat variation in these loci in nine ethnic sub-populations of eastern India from which the patients originated. We report here that the frequency of large normal alleles (>31 CAG repeats) in SCA1 locus to be 0.211 of 394 chromosomes studied. We also report that the frequency of large normal alleles (>22 CAG repeats) at the SCA2 locus is 0.038 while at the SCA6 locus frequency of large normal alleles (>13 repeats) is 0.032. We discussed our data in light of the distribution of normal alleles and prevalence of SCAs in the Japanese and white populations.