Molecular genetics of hereditary spinocerebellar ataxia: mutation analysis of spinocerebellar ataxia genes and CAG/CTG repeat expansion detection in 225 Italian families.

Abstract

BACKGROUND:

Autosomal dominant cerebellar ataxias are a clinical and genetically heterogeneous group of progressive neurodegenerative diseases, at present associated with 22 loci (spinocerebellar ataxia [SCA] 1-SCA8, SCA10-SCA19, SCA21, SCA22, fibroblast growth factor 14 [FGF14]-SCA, and dentatorubral-pallidoluysian atrophy [DRPLA]). The relevant gene has been identified in 12 cases (SCA1-3, SCA6-8, SCA10, SCA12, FGF14, and DRPLA), and in all but the recently identified SCA14, SCA17, PRKCG and FGF14 genes, the defect consists of the expansion of a short nucleotide repeat.

OBJECTIVES:

To investigate the relative prevalence of SCA1-3, SCA6-8, SCA10, SCA12, and SCA17 gene expansions in Italian families with hereditary ataxia, specifically to verify the occurrence of SCA10, SCA12, and SCA17 in Italy; and to analyze samples from probands with negative test results at the initial screening by means of the repeat expansion detection technique to identify CAG/CTG expansions in novel loci.Patients Two hundred twenty-five unrelated Italian index cases with hereditary ataxia, most (n = 183) of whom presented with a clear dominantly transmitted trait.

RESULTS:

We found that SCA1 and SCA2 gene mutations accounted for most cases (21% and 24%, respectively). We found SCA3, SCA6, SCA7, SCA8, and SCA17 to be very rare (approximately 1% each), and no case of SCA10 or SCA12 was identified. Half of the index cases (113/225) were negative for expansions in the known SCA genes. Repeat expansion detection analysis performed on 111 of these cases showed a CAG/CTG repeat expansion of at least 50 triplets in 22 (20%). Twenty-one of 22 expansions could be attributed to length variation at 2 polymorphic loci (expanded repeat domain CAG/CTG 1 [ERDA1] or CTG repeat on chromosome 18q21.1 [CTG18.1]). In 1 patient, the expansion was assigned to the DRPLA gene.

CONCLUSIONS:

The distribution of SCA1-3 and SCA6-7 gene mutations is peculiar in Italy. We found a relatively high frequency of SCA1 and SCA2 gene expansions; SCA3, SCA6, and SCA7 mutations were rare, compared with other European countries. No SCA10 or SCA12 and only a few SCA8 (2/225) and SCA17 (2/225) families were detected. In patients negative for defects in known SCA genes, repeat expansion detection data strongly suggest that, at least in our population, CAG/CTG expansions in novel genes should be considered an unlikely cause of the SCA phenotype.

• Authors: Alfredo Brusco, Cinzia Gellera, Claudia Cagnoli, Alessandro Saluto, Alessia Castucci, Chiara Michielotto, Vincenza Fetoni, Caterina Mariotti, Nicola Migone, Stefano Di Donato, Franco Taroni
• Journal: Archives of neurology (Arch Neurol) Vol. 61 Issue 5 Pg. 727-33 (May 2004) ISSN: 0003-9942 [Print] United States
• PMID: 15148151 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATXN1 protein, human
• ATXN7 protein, human
• ATXN8OS gene product, human
• Ataxin-1
• Ataxin-7
• Ataxins
• CACNA1A protein, human
• Calcium Channels
• Nerve Tissue Proteins
• Nuclear Proteins
• Proteins
• RNA, Long Noncoding
• RNA, Untranslated
• Repressor Proteins
• ATXN3 protein, human
• Ataxin-3

Topics

• Adult
• Aged
• Ataxin-1
• Ataxin-3
• Ataxin-7
• Ataxins
• Calcium Channels (genetics)
• DNA Mutational Analysis
• Female
• Humans
• Italy
• Male
• Microsatellite Repeats
• Middle Aged
• Molecular Biology
• Nerve Tissue Proteins (genetics)
• Nuclear Proteins (genetics)
• Pedigree
• Polymerase Chain Reaction
• Proteins (genetics)
• RNA, Long Noncoding
• RNA, Untranslated
• Repressor Proteins
• Spinocerebellar Ataxias (genetics)
• Trinucleotide Repeat Expansion