Molecular Genetics of Hereditary Spinocerebellar Ataxia: Mutation Analysis of Spinocerebellar Ataxia Genes and CAG/CTG Repeat Expansion Detection in 225 Italian Families

Alfredo Brusco, Cinzia Gellera, Claudia Cagnoli, Alessandro Saluto, Alessia Castucci, Chiara Michielotto, Vincenza Fetoni, Caterina Mariotti, Nicola Migone, Stefano Di Donato, Franco Taroni

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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, SCA14, SCA17, FGF14, and DRPLA), and in all but the recently identified 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.

Original languageEnglish
Pages (from-to)727-733
Number of pages7
JournalArchives of Neurology
Volume61
Issue number5
DOIs
Publication statusPublished - May 2004

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Spinocerebellar Degenerations
Spinocerebellar Ataxias
Molecular Biology
Mutation
Genes
Progressive Myoclonic Epilepsy
Italy
Repeats
Molecular Genetics
Gene
Cerebellar Ataxia
Neurodegenerative Diseases
Nucleotides
Chromosomes

ASJC Scopus subject areas

  • Neuroscience(all)

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Molecular Genetics of Hereditary Spinocerebellar Ataxia : Mutation Analysis of Spinocerebellar Ataxia Genes and CAG/CTG Repeat Expansion Detection in 225 Italian Families. / Brusco, Alfredo; Gellera, Cinzia; Cagnoli, Claudia; Saluto, Alessandro; Castucci, Alessia; Michielotto, Chiara; Fetoni, Vincenza; Mariotti, Caterina; Migone, Nicola; Di Donato, Stefano; Taroni, Franco.

In: Archives of Neurology, Vol. 61, No. 5, 05.2004, p. 727-733.

Research output: Contribution to journalArticle

Brusco, Alfredo ; Gellera, Cinzia ; Cagnoli, Claudia ; Saluto, Alessandro ; Castucci, Alessia ; Michielotto, Chiara ; Fetoni, Vincenza ; Mariotti, Caterina ; Migone, Nicola ; Di Donato, Stefano ; Taroni, Franco. / Molecular Genetics of Hereditary Spinocerebellar Ataxia : Mutation Analysis of Spinocerebellar Ataxia Genes and CAG/CTG Repeat Expansion Detection in 225 Italian Families. In: Archives of Neurology. 2004 ; Vol. 61, No. 5. pp. 727-733.
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title = "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, SCA14, SCA17, FGF14, and DRPLA), and in all but the recently identified 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.",
author = "Alfredo Brusco and Cinzia Gellera and Claudia Cagnoli and Alessandro Saluto and Alessia Castucci and Chiara Michielotto and Vincenza Fetoni and Caterina Mariotti and Nicola Migone and {Di Donato}, Stefano and Franco Taroni",
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TY - JOUR

T1 - Molecular Genetics of Hereditary Spinocerebellar Ataxia

T2 - Mutation Analysis of Spinocerebellar Ataxia Genes and CAG/CTG Repeat Expansion Detection in 225 Italian Families

AU - Brusco, Alfredo

AU - Gellera, Cinzia

AU - Cagnoli, Claudia

AU - Saluto, Alessandro

AU - Castucci, Alessia

AU - Michielotto, Chiara

AU - Fetoni, Vincenza

AU - Mariotti, Caterina

AU - Migone, Nicola

AU - Di Donato, Stefano

AU - Taroni, Franco

PY - 2004/5

Y1 - 2004/5

N2 - 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, SCA14, SCA17, FGF14, and DRPLA), and in all but the recently identified 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.

AB - 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, SCA14, SCA17, FGF14, and DRPLA), and in all but the recently identified 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.

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