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. 2000 Mar;66(3):830-40.
doi: 10.1086/302827.

High germinal instability of the (CTG)n at the SCA8 locus of both expanded and normal alleles

I Silveira  1 , I Alonso, L Guimarães, P Mendonça, C Santos, P Maciel, J M Fidalgo De Matos, M Costa, C Barbot, A Tuna, J Barros, L Jardim, P Coutinho, J Sequeiros
Affiliations

High germinal instability of the (CTG)n at the SCA8 locus of both expanded and normal alleles

I Silveira et al. Am J Hum Genet. 2000 Mar.

Abstract

The autosomal dominant spinocerebellar ataxias (SCAs) are a group of late-onset, neurodegenerative disorders for which 10 loci have been mapped (SCA1, SCA2, SCA4-SCA8, SCA10, MJD, and DRPLA). The mutant proteins have shown an expanded polyglutamine tract in SCA1, SCA2, MJD/SCA3, SCA6, SCA7, and DRPLA; a glycine-to-arginine substitution was found in SCA6 as well. Recently, an untranslated (CTG)n expansion on chromosome 13q was described as being the cause of SCA8. We have now (1) assessed the repeat size in a group of patients with ataxia and a large number of controls, (2) examined the intergenerational transmission of the repeat, and (3) estimated the instability of repeat size in the sperm of one patient and two healthy controls. Normal SCA8 chromosomes showed an apparently trimodal distribution, with classes of small (15-21 CTGs), intermediate (22-37 CTGs), and large (40-91 CTGs) alleles; large alleles accounted for only0.7% of all normal-size alleles. No expanded alleles (>/=100 CTGs) were found in controls. Expansion of the CTG tract was found in five families with ataxia; expanded alleles (all paternally transmitted) were characterized mostly by repeat-size contraction. There was a high germinal instability of both expanded and normal alleles: in one patient, the expanded allele (152 CTGs) had mostly contraction in size (often into the normal range); in the sperm of two normal controls, contractions were also more frequent, but occasional expansions into the upper limit of the normal size range were also seen. In conclusion, our results show (1) no overlapping between control (15-91) and pathogenic (100-152) alleles and (2) a high instability in spermatogenesis (both for expanded and normal alleles), suggesting a high mutational rate at the SCA8 locus.

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Figures

Figure 1
Figure 1
Pedigrees and genotyping from four families with SCA8. Circles and squares with black dots indicate asymptomatic carriers of expanded alleles. Haplotypes of four microsatellite markers spanning 2 cM within the SCA8-locus region are shown. The haplotype that segregates with the expansion is boxed, and inferred haplotypes are bracketed. The (CTG)n (position unknown) was arbitrarily positioned as being telomeric to all markers. The fifth family (BR) is not shown, since no family genotyping was available.
Figure 2
Figure 2
Pedigree and PCR products of family CH. Genomic DNA was amplified by use of primers SCA8-F4 and SCA8-R4. PCR products were analyzed on 6% polyacrylamide gels. Allele sizes were determined by comparison of migration relative to an M13 sequencing ladder. Normal alleles had sizes varying from 15 to 91 units, and expanded alleles varied from 100 to 170.
Figure 3
Figure 3
Distribution of CTG repeat size of alleles at the SCA8 locus in a normal population of Portuguese origin (n=1,818).
Figure 4
Figure 4
Low-copy PCR of sperm cells. DNA was amplified with primers SCA8-F4 and SCA8-R4 and analyzed on 6% polyacrylamide gels. Allele sizes were determined by comparison of migration relative to a M13 sequencing ladder. A, Patient with alleles of 152 and 28 repeats in peripheral blood; alleles with ⩽37 CTGs were assumed to have derived from the 28-repeat allele. B, Healthy control, homozygote for a 25-repeat allele on blood leukocytes; similar results (not shown) were obtained with another healthy control with 25/23 CTGs in peripheral leukocytes.
Figure 5
Figure 5
A, Frequency of variation in repeat size of a 152-repeat SCA8 allele in sperm cells of a heterozygous patient with 152/28 CTGs; the arrow indicates the length of the donor’s allele in peripheral blood leukocytes (alleles with ⩽37 CTGs are not shown, since they were assumed to be derived from the 28-repeat allele). B, Distribution of repeat-size changes during meiosis (determined by subtracting the size of repeats in leukocytes to that in sperm).
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References

Electronic-Database Information

    1. Center for Medical Genetics database, http://www.marshmed.org/genetics
    1. Fondation Jean Dausset CEPH database, http://www.cephb.fr
    1. Généthon, http://www.genethon.fr
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nim.nih.gov/omim (for SCA8 [MIM 603680]) - PubMed

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