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


OBJECTIVE
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.
Brusco
Alfredo
A
Dipartimento di Genetica, Biologia e Biochimica, Università di Torino and Unitá Operativa Genetica Medica, Ospedale San Giovanni Battista di Torino, Torino, Italy. alfredo.brusco@unito.it
Gellera
Cinzia
C
Cagnoli
Claudia
C
Saluto
Alessandro
A
Castucci
Alessia
A
Michielotto
Chiara
C
Fetoni
Vincenza
V
Mariotti
Caterina
C
Migone
Nicola
N
Di Donato
Stefano
S
Taroni
Franco
F
D000328:Adult; D000368:Aged; D000067696:Ataxin-1; D000067699:Ataxin-3; D000067719:Ataxin-7; D000067528:Ataxins; D015220:Calcium Channels / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007558:Italy; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D008967:Molecular Biology; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D012097:Repressor Proteins; D020754:Spinocerebellar Ataxias / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion; D020864:Calcium Channels, N-Type
D000067696:Ataxin-1; D000067699:Ataxin-3; D000067719:Ataxin-7; D000067528:Ataxins; D015220:Calcium Channels; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011506:Proteins; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D012097:Repressor Proteins; C000593749:ATXN1 protein, human; C000593829:ATXN7 protein, human; C415906:ATXN8OS gene product, human; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type; C092341:ATXN3 protein, human