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SCA8 Repeat Expansion Coexists with SCA1—Not Only with SCA6

2003; Elsevier BV; Volume: 73; Issue: 4 Linguagem: Inglês

10.1086/378524

1537-6605

Anna Sułek, Dorota Hoffman‐Zacharska, Elżbieta Zdzienicka, Jacek Zaremba,

Mitochondrial Function and Pathology

To the Editor: Izumi et al. (Izumi et al., 2003Izumi Y Maruyama H Oda M Morino H Okada T Ito H Sasaki I Tanaka H Komure O Udaka F Nakamura S Kawakami H SCA8 repeat expansion: large CTA/CTG repeat alleles are more common in ataxic patients, including those with SCA6.Am J Hum Genet. 2003; 72: 704-709Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar) observed coexistence of the expanded spinocerebellar ataxia (SCA) type 8 (SCA8 [MIM 603680]) CTA/CTG repeat alleles and large SCA6 (MIM 183068) CAG repeat alleles. They speculated that the presence of the expanded SCA8 alleles could influence the function of the α1A-voltage-dependent calcium channel gene (CACNA1A [MIM 601011]), the expanded CAG repeat of which is responsible for SCA6. In 2 of 127 (1.6%) families with SCA6, Izumi et al. (Izumi et al., 2003Izumi Y Maruyama H Oda M Morino H Okada T Ito H Sasaki I Tanaka H Komure O Udaka F Nakamura S Kawakami H SCA8 repeat expansion: large CTA/CTG repeat alleles are more common in ataxic patients, including those with SCA6.Am J Hum Genet. 2003; 72: 704-709Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar) observed large expanded SCA8 alleles (⩾85 CTA/CTG repeats), and, in 3 families, they observed intermediate-sized alleles (50–84 CTA/CTG repeats). Altogether, expanded SCA8 alleles were present in 5 of 127 (3.9%) families with SCA6. The authors wrote that coexistence with SCA8 expanded alleles may be “specific to SCA6 and is not seen in other…ataxias with CAG repeat expansions” (p. 707) (they have not found expanded SCA8 alleles in 118 families with SCA3/Machado-Joseph disease [MIM 607047] or in 45 families with SCA1 [MIM 164400], SCA2 [MIM 183090], SCA7 [MIM 164500], SCA17 [MIM 607136], or dentatorubral-pallidoluysian atrophy [MIM 125370]). Therefore, they suggested that there could be an interaction of the SCA6 and SCA8 genes and that the SCA6 locus/product “should be included in a pathway of appearance of SCA8 phenotype” (p. 708). Here, we want to show that expanded SCA8 alleles may be present in SCA1, as well. In a group of 58 Polish families with 101 molecularly confirmed cases of SCA1, we observed 5 (8.6%) families with expanded SCA8 CTA/CTG alleles, with repeat numbers ranging from 53 to 116 (table 1). The data presented in table 1 show that: 1.each subject with the expanded SCA1 CAG repeat was affected with SCA1;2.in four patients (II-1, II-3, II-4, and III-3), only expanded SCA1 alleles were present;3.in four unaffected subjects (I-3, II-2, III-1, and IV-2) with normal ranges of SCA1 CAG repeats, only expanded SCA8 alleles were present;4.in two of the families with SCA1, the expanded SCA8 CTA/CTG repeat alleles were present only in unaffected subjects with normal number, of SCA1 CAG repeats (families II and III); and5.in three patients (I-1, IV-1, and V-1), coexistence of expanded SCA1 and SCA8 alleles was observed, but their relatively early ages at onset of the disease appeared to depend on the number of SCA1 CAG repeats rather than on the presence of SCA8 CTA/CTG expanded alleles (compare, for instance, subjects II-3 and IV-1).Table 1Pedigrees with SCA1 in Whom Expanded CTA/CTG SCA8 Alleles Were Observed in Affected and Unaffected SubjectsPedigreeStatusSCA1: CAG Repeat LengthaThe pathogenic SCA1 alleles range from 40 to 80 repeats and contain only uninterrupted CAG stretches; the nonpathogenic SCA1 CAG repeat alleles range from 6 to 39 repeats and contain a midstream CAT interruption (Orr et al. 1993; Chung et al. 1993).SCA8: CTA/CTG Repeat LengthbIzumi et al. (2003) tentatively classified the expanded CAT/CTG SCA8 alleles into intermediate-sized (50–84 repeats), large (85–399 repeats), and very large (⩾400 repeats).Ages at Examination/Onset (years)I-1Affected57/3277/1850/30I-2Unaffected30/3018/1818/…I-3Unaffected32/3080/1847/…II-1Affected51/3329/1844/40II-2Unaffected33/3087/1822/…II-3Affected64/3329/1826/19II-4Affected53/3023/2339/37III-1Unaffected31/3069/2433/…III-2Unaffected31/2927/1819/…III-3Affected50/39/31cA case of mosaicism (three SCA1 alleles) in DNA extracted from blood of the affected individual (III-3).27/2457/35IV-1Affected65/30113/2423/20IV-2Unaffected32/30116/2420/…IV-3Unaffected32/3028/2445/…V-1Affected54/3253/1835/30Note.—Intermediate-sized SCA8 CTA/CTG repeats were observed in four subjects (two affected with SCA1 and two unaffected); large SCA8 CTA/CTG repeats were observed in three subjects (one affected with SCA1 and two unaffected).a The pathogenic SCA1 alleles range from 40 to 80 repeats and contain only uninterrupted CAG stretches; the nonpathogenic SCA1 CAG repeat alleles range from 6 to 39 repeats and contain a midstream CAT interruption (Orr et al. Orr et al., 1993Orr HT Chung MY Banfi S Kwiatkowski TJJ Servadio A Beaudet AL McCall AE Duvick LA Ranum LP Zoghbi HY Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1.Nat Genet. 1993; 4: 221-226Crossref PubMed Scopus (1409) Google Scholar; Chung et al. Chung et al., 1993Chung MY Ranum LP Duvick LA Servadio A Zoghbi HY Orr HT Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type 1.Nat Genet. 1993; 5: 254-258Crossref PubMed Scopus (417) Google Scholar).b Izumi et al. (Izumi et al., 2003Izumi Y Maruyama H Oda M Morino H Okada T Ito H Sasaki I Tanaka H Komure O Udaka F Nakamura S Kawakami H SCA8 repeat expansion: large CTA/CTG repeat alleles are more common in ataxic patients, including those with SCA6.Am J Hum Genet. 2003; 72: 704-709Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar) tentatively classified the expanded CAT/CTG SCA8 alleles into intermediate-sized (50–84 repeats), large (85–399 repeats), and very large (⩾400 repeats).c A case of mosaicism (three SCA1 alleles) in DNA extracted from blood of the affected individual (III-3). Open table in a new tab Note.— Intermediate-sized SCA8 CTA/CTG repeats were observed in four subjects (two affected with SCA1 and two unaffected); large SCA8 CTA/CTG repeats were observed in three subjects (one affected with SCA1 and two unaffected). The rate of coexistence of the expanded SCA1 and SCA8 alleles in the entire group of patients with SCA1 was 3%. The above data show that, although the expanded alleles of SCA8 may be present in families with SCA1, the role of the alleles as a modifying factor in SCA1 is uncertain or doubtful and, judging from the data of Izumi et al. (Izumi et al., 2003Izumi Y Maruyama H Oda M Morino H Okada T Ito H Sasaki I Tanaka H Komure O Udaka F Nakamura S Kawakami H SCA8 repeat expansion: large CTA/CTG repeat alleles are more common in ataxic patients, including those with SCA6.Am J Hum Genet. 2003; 72: 704-709Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar), less important than in SCA6. Among 650 patients referred to us with the diagnosis of SCA, we also came across seven families with 18 (9 affected and 9 unaffected) subjects with expanded SCA8 alleles in the range of 79–150 CTA/CTG repeats; other types of SCAs with CAG expansions (SCA1, SCA2, SCA3, SCA6, SCA7, SCA12 [MIM 604326], SCA-17, and DRPLA) were excluded in these families. We did not find SCA8 expanded alleles in any of the 26 cases of SCA2 or in 2 cases from one family with SCA17. Other types of SCA have not been detected in Poland; the absence of SCA3 is particularly striking, since it is relatively common in western Europe. Until now, we did not find homozygotes for expanded SCA8 alleles among Polish patients with SCA. We would also like to mention that, in a group consisting of 250 subjects (mean age ± SD: 58.8 ± 20.7) with different forms of hyperlipidemia but with no history of neurological disorders, we found three subjects carrying large SCA8 alleles of 91, 95, and 100 CTA/CTG repeats. We did not find any case of the expanded SCA8 alleles in a group of 100 patients affected with Huntington disease (MIM 143100). Our data, like those of the Japanese study, show that expanded SCA8 CTA/CTG alleles tend to be more frequent in the group of patients with SCA and in members of their families. The difference between the Polish and Japanese data is in our observation of SCA8 allele expansions in some families with SCA1 (table 1). The two data sets, the Japanese and the Polish, seem to be complementary to each other and suggestive of a possible transacting factor role for the SCA8 locus in the expansion mechanism in SCA repeat disorders; Izumi et al. (Izumi et al., 2003Izumi Y Maruyama H Oda M Morino H Okada T Ito H Sasaki I Tanaka H Komure O Udaka F Nakamura S Kawakami H SCA8 repeat expansion: large CTA/CTG repeat alleles are more common in ataxic patients, including those with SCA6.Am J Hum Genet. 2003; 72: 704-709Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar) proposed a possible pathomechanism with SCA8 locus involvement in SCA6—the disease caused by the mutation of the gene, the product of which has a known function—but their hypothesis needs to be confirmed. The role of the expanded SCA8 locus in other types of SCA, including SCA1 and SCA8—which is not yet a very distinctly defined genetic entity—remains to be established. Our study on SCAs was supported by State Committee for Scientific Research grant 4 P05E 096 18.