Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion

Abstract

The gene for spinocerebellar ataxia 7 (SCA7) has been mapped to chromosome 3p12-13. By positional cloning, we have identified a new gene of unknown function containing a CAG repeat that is expanded in SCA7 patients. On mutated alleles, CAG repeat size is highly variable, ranging from 38 to 130 repeats, whereas on normal alleles it ranges from 7 to 17 repeats. Gonadal instability in SCA7 is greater than that observed in any of the seven known neuro-degenerative diseases caused by translated CAG repeat expansions, and is markedly associated with paternal transmissions. SCA7 is the first such disorder in which the degenerative process also affects the retina.

Spectrum and prevalence of autosomal dominant spinocerebellar ataxia in Hokkaido, the northern island of Japan: a study of 113 Japanese families

“…Expanded triplet repeats in the genes causing SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, and DRPLA were amplified using the primer pairs Rep-1/ Rep-2 (Orr et al 1993), F-1/F-2 (Sanpei et al 1996), MJD25/ MJD52 (Kawaguchi et al 1994), S-5-F1/ S-5-R1 (Zhunchenko et al 1997), 4U1024/4U716 (David et al 1997), SCA8-F3/SCA8-R4 (Koob et al 1999), PPP2R2B-A/PPP2R2B-B (Holmes et al 1999), TBP-F/TBP-R (Nakamura et al 2001) and CTG-B37(699)/(840) (Koide et al 1994) respectively. We did not test for the SCA10 mutation, because its clinical manifestation is ataxia with seizure, which was not observed in our ADCA families.…”

“…(Matsuura et al 2000); SCA11 on 15q14-q21.3 (Worth et al 1999); SCA12 on 5q31-33 (Holmes et al 1999);SCA13 on 19q13.3-q13.4 (Waters et al 2006); SCA14 on 19q13.42 Chen et al 2003;Yabe et al 2003); SCA15 on 3p24.2 (Gardner et al 2005); SCA16 on 8q23-q24.1 (Miyoshi et al 2001); SCA17 on 6q27 (Nakamura et al 2001); SCA18 on 7q22 (Brkanac et al 2002); SCA19 on 1p21-q21 (Verbeek et al 2002); SCA20 on 11p11.2-q13.3 (Knight et al 2004); SCA21 on 7p21.3-p15.1 (Vuillaume et al 2002); SCA22 on 1p21-q23 (Chung et al 2003); SCA23 on 20p13-p12 (Verbeek et al 2004); SCA24 on 1p26 (Swartz et al 2002); SCA25 on 2p21-p15 (Stevanin et al 2004); SCA26 on 19p13.3 (Yu et al 2005); SCA27 on 13q33.1 (Van Swieten et al 2003); SCA28 on 18p11.22-q11.2 (Cagnoli et al 2006); SCA 29 on 3p26 (Dudding et al 2004) and dentatorubral pallidoluysian atrophy (DRPLA) on 12p13.31 (Koide et al 1994;Nagafuchi et al 1994). Among these loci, causative genes have been further identified containing trinucleotide repeats (CAG) in SCA1, SCA2, SCA3, SCA6, SCA7, SCA17, DRPLA (Orr et al 1993;Sanpei et al 1996;Kawaguchi Y et al 1994;Zhuchenko et al 1997;David et al 1997;Nakamura et al 2001;Koide et al 1994), and in the promoter region of PPP2R2B related to SCA12 (Holmes et al 1999); trinucleotide repeats (CTG) within an untranslated region of the SCA8 gene (Koob et al 1999); and a pentanucleotide (ATTCT) repeat expansion within intron 9 of the SCA10 gene (Matsuura et al 2000). Whi...…”

“…ADCA type I is variably associated with ataxia of the gait, ophthalmoplegia, pyramidal and extrapyramidal signs, cognitive impairment, optic atrophy or peripheral neuropathy; ADCA type II with retinopathy; and ADCA type III with late onset, pure cerebellar ataxia with genetic heterogeneity. To date, 29 different genetic loci have been reported to be responsible for ADCA (http://www.gene.ucl.ac.uk/cgi-bin/nomenclature): spinocerebellar ataxia type 1 (SCA1) on chromosome 6p22-p23 (Orr et al 1993); SCA2 on 12q23-q24.1 (Imbert et al 1996;Sanpei et al 1996); Machado-Joseph disease (MJD)/ SCA3 on 14q24.3-q32.1 (Kawaguchi et al 1994); SCA4 on 16q22.1 (Flanigan et al 1996); SCA5 on 11q13.2 (Ranum et al 1994); SCA6 on 19p13.1 (Zhuchenko et al 1997); SCA7 on 3p12-p13 (David et al 1997); SCA8 on 13p (Koob et al 1999); SCA10 on 22q13-qter. (Matsuura et al 2000); SCA11 on 15q14-q21.3 (Worth et al 1999); SCA12 on 5q31-33 (Holmes et al 1999);SCA13 on 19q13.3-q13.4 (Waters et al 2006); SCA14 on 19q13.42 Chen et al 2003;Yabe et al 2003); SCA15 on 3p24.2 (Gardner et al 2005); SCA16 on 8q23-q24.1 (Miyoshi et al 2001); SCA17 on 6q27 (Nakamura et al 2001); SCA18 on 7q22 (Brkanac et al 2002); SCA19 on 1p21-q21 (Verbeek et al 2002); SCA20 on 11p11.2-q13.3 (Knight et al 2004); SCA21 on 7p21.3-p15.1 (Vuillaume et al 2002); SCA22 on 1p21-q23 (Chung et al 2003); SCA23 on 20p13-p12 (Verbeek et al 2004); SCA24 on 1p26 (Swartz et al 2002); SCA25 on 2p21-p15 (Stevanin et al 2004); SCA26 on 19p13.3 (Yu et al 2005); SCA27 on 13q33.1 (Van Swieten et al 2003); SCA28 on 18p11.22-q11.2 (Cagnoli et al 2006); SCA 29 on 3p26 (Dudding et al 2004) and dentatorubral pallidoluysian atrophy (DRPLA) on 12p13.31 <...>…”

Regional features of autosomal-dominant cerebellar ataxia in Nagano: clinical and molecular genetic analysis of 86 families

“…Initial denaturation at 95°C for 1 min was followed by 30 cycles of denaturation for 30 s at 95°C, annealing for 30 s at 60°C, extension for 30 s at 72°C, and a final extension step at 72°C for 7 min. The gene-specific primers used in this study have already been published (Orr et al 1993;Imbert et al 1996;Pulst et al 1996;Sanpei et al 1996;Kawaguchi et al 1994;Zhuchenko et al 1997;David et al 1997;Holmes et al 1999;Nakamura et al 2001;Koide et al 1994;Nagafuchi et al 1994). The PCR products were run with an ALF express Sizer 50-500 (Pharmacia Bioscience) in Urea gel (final conc.…”

Spinocerebellar ataxias: microsatellite and allele frequency in unaffected and affected individuals

“…The number of CAG trinucleotide repeats varies from one population to another [2][3][4] . In normal individuals, SCA 1 alleles range from 6 to 39 CAG repeats (CAGn) [5][6][7][8] ; in SCA2 alleles range from 15 to 24 CAGn 9-11 ; in SCA3 (Machado Joseph disease -MJD) from 13 to 41 CAGn [12][13][14] ; in SCA6¨from 6 to 16 CAGn [15][16] , and in SCA7 ranges from 4 to 17 CAGn [17][18] . Intermediate alleles are found in studies with families which have not been described in the normal population.…”