CAG repeat instability at SCA2 locus: anchoring CAA interruptions and linked single nucleotide polymorphisms. Hum Mol Genet

Functional Genomics Unit, Centre for Biochemical Technology (CSIR), Mall Road, Delhi, India.
Human Molecular Genetics (Impact Factor: 6.39). 11/2001; 10(21):2437-46. DOI: 10.1093/hmg/10.21.2437
Source: PubMed


Spinocerebellar ataxia 2 (SCA2) is an autosomal dominant neurodegenerative disorder that results from the expansion of a cryptic CAG repeat within the exon 1 of the SCA2 gene. The CAG repeat in normal individuals varies in length from 14 to 31 repeats and is frequently interrupted by one or more CAA triplets, whereas the expanded alleles contain a pure uninterrupted stretch of 34 to 59 CAG repeats. We have previously reported the presence of a limited pool of 'ancestral' or 'at risk' haplotypes for the expanded SCA2 alleles in the Indian population. We now report the identification of two novel single nucleotide polymorphisms (SNPs) in exon 1 of the SCA2 gene and their characterization in 215 normal and 64 expanded chromosomes. The two biallelic SNPs distinguished two haplotypes, GT and CC, each of which formed a predominant haplotype associated with normal and expanded SCA2 alleles. All the expanded alleles segregated with CC haplotype, which otherwise was associated with only 29.3% of the normal chromosomes. CAA interspersion analysis revealed that majority of the normal alleles with CC haplotype were either pure or lacked the most proximal 5' CAA interruption. The repeat length variation at SCA2 locus also appeared to be polar with changes occurring mostly at the 5' end of the repeat. Our results demonstrate that CAA interruptions play an important role in conferring stability to SCA2 repeat and their absence predisposes alleles towards instability and pathological expansion. Our study also provides new haplotypes associated with SCA2 that should prove useful in further understanding the mutational history and mechanism of repeat instability at the SCA2 locus.

Download full-text


Available from: Achal Kumar Srivastava, Aug 14, 2014
  • Source
    • "The CTG repeat at DMPK locus is usually uninterrupted in both healthy and expanded alleles, however so called " variant " repeats containing unstable CCG, CTC and CGG sequence interruptions at the 3′-end of the CTG array can be detected in a low percentage (3–5% of cases) of DM1 patients [23] [24] [25] [26]. The presence of interruptions within an otherwise homogeneous tract of repeats has been associated with a number of TREDs including FRAXA [27], SCA1 [28], SCA2 [29] and FRDA [30] [31]. In general, repeat interruptions lead to a stabilizing effect because of their ability to disrupt the formation of unusual DNA structures formed by " pure " repetitive sequences [32]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A differential CpGmethylation profile upstreamof the expanded CTG array at the DMPK locus has been reported in patientswithmyotonic dystrophy type 1 (DM1), suggesting that hypermethylationmightmodulate DM1 phenotype, possibly affecting expression levels of DMPK and/or flanking genes. To clarify this issue,we characterized by methylation sensitive high resolution melting (MS-HRM) the CpG methylation pattern of DNA sequences flanking the pathological CTG expansion in 13 childhood-onset, 37 juvenile/adult-onset, 7 congenital DM1 pa- tients carrying uninterrupted CTG expansions and in 9 DM1 patients carrying variant expansions vs 30 controls. Association of methylation status with disease features (nCTG, age, sex, MIRS, disease duration) was also assessed. Finally, DMPK and SIX5 expression levels were evaluated in leukocytes from controls, methylated and unmethylated DM1 patients. We found hypermethylation involving upstreamsequences of DM1 locus in patientswith uninterrupted CTG ex- pansions N1000 CTG and affected by a congenital or childhood onset form. Besides the n(CTG) and early disease onset, hypermethylation was also significantly associated with maternal transmission. On the other hand, hypermethylation involved the 3' of the CTG array in DM1 patients carrying variant expan-sions. DMPK and SIX5 expression did not significantly differ in methylated vs unmethylated DM1 patients. Our results suggest that either the inherited size of the expanded allele and the presence of interruptions at the 3' end are associated with a highly polarized pattern of CpGmethylation at the DM1 locus and that, at least in leukocytes, DM1 locus hypermethylation would not significantly affect DMPK or SIX5 expression.
    Biochimica et Biophysica Acta 09/2015; 1852(12). DOI:10.1016/j.bbadis.2015.09.007 · 4.66 Impact Factor
  • Source
    • "This finding has been confirmed by other similar observations [47]. The ATXN2 gene without CAA triplets, which stabilizes the CAG repeats [79], may produce ataxin-2 protein with longer PolyQ repeats which is more toxic to the host cells, compared to the ataxin-2 protein produced by the gene with the CAA triplet. This type of triplet is less common in longer CAG repeats in the ATXN2 gene in SCA2 patients [46], [69], [80], [81]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a rare degenerative condition of the motor neurons. Over 10% of ALS cases are linked to monogenic mutations, with the remainder thought to be due to other risk factors, including environmental factors, genetic polymorphisms, and possibly gene-environmental interactions. We examined the association between ALS and an intermediate CAG repeat expansion in the ATXN2 gene using a meta-analytic approach. Observational studies were searched with relevant disease and gene terms from MEDLINE, EMBASE, and PsycINFO from January 2010 through to January 2014. All identified articles were screened using disease terms, gene terms, population information, and CAG repeat information according to PRISMA guidelines. The final list of 17 articles was further evaluated based on the study location, time period, and authors to exclude multiple usage of the same study populations: 13 relevant articles were retained for this study. The range 30-33 CAG repeats in the ATXN2 gene was most strongly associated with ALS. The meta-analysis revealed that the presence of an intermediate CAG repeat (30-33) in the ATXN2 gene was associated with an increased risk of ALS [odds ratio (OR) = 4.44, 95%CI: 2.91-6.76)] in Caucasian ALS patients. There was no significant difference in the association of this CAG intermediate repeat expansion in the ATXN2 gene between familial ALS cases (OR = 3.59, 1.58-8.17) and sporadic ALS cases (OR = 3.16, 1.88-5.32). These results indicate that the presence of intermediate CAG repeat expansion in the ATXN2 gene is a specific genetic risk factor for ALS, unlike monogenic mutations with an autosomal dominant transmission mode, which cause a more severe phenotype of ALS, with a higher prevalence in familial ALS.
    PLoS ONE 08/2014; 9(8):e105534. DOI:10.1371/journal.pone.0105534 · 3.23 Impact Factor
  • Source
    • "conferring stability to ATXN2 repeat and their absence predisposes alleles towards instability and pathological expansion . A minimal length of pure repeats is required to initiate instability, and the presence of interruptions break the repeat into smaller repeat tracts and thus protects it from instability by reducing the length of continuous uninterrupted repeats (Choudhry et al. 2001). Individual V.2 is the only one in the family with a 33 repeats allele (genotype 22/33). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In 2001 a program for predictive testing of Spinocerebellar Ataxia type 2 was developed in Cuba, based on the detection of an abnormal CAG trinucleotide repeat expansion in the ATXN2 gene. A descriptive study was designed to assess the implications of ATXN2 large normal and intermediate alleles in the context of the SCA2 Prenatal Diagnosis Program. Four clinical scenarios were selected based upon the behaviour of large normal and intermediate alleles when passing from one generation to the next, showing expansions, contractions, or stability in the CAG repeat size. In some populations, traditional Mendelian risk figures of 0 % or 50 % may not be applicable due to the high frequency of unstable large normal alleles. Couples with no family history of SCA2 may have a >0 % risk of having an affected offspring. Similarly, couples in which there is both an expanded and a large normal allele may have a recurrence risk >50 %. It is imperative that these issues be addressed with these couples during genetic counseling. These recurrence risks have to be carefully estimated in the presence of such alleles (particularly alleles ≥27 CAG repeats), carriers need to be aware of the potential risk for their descendants, and programs for prenatal diagnosis must be available for them.
    Journal of Genetic Counseling 06/2013; 23(1). DOI:10.1007/s10897-013-9615-1 · 2.24 Impact Factor
Show more