Missense mutations in the AFG3L2 proteolytic domain account for â¼1.5% of European autosomal dominant cerebellar ataxias.
Hum Mutat
; 31(10): 1117-24, 2010 Oct.
Article
em En
| MEDLINE
| ID: mdl-20725928
ABSTRACT
Spinocerebellar ataxia type 28 is an autosomal dominant form of cerebellar ataxia (ADCA) caused by mutations in AFG3L2, a gene that encodes a subunit of the mitochondrial m-AAA protease. We screened 366 primarily Caucasian ADCA families, negative for the most common triplet expansions, for point mutations in AFG3L2 using DHPLC. Whole-gene deletions were excluded in 300 of the patients, and duplications were excluded in 129 patients. We found six missense mutations in nine unrelated index cases (9/366, 2.6%) c.1961C>T (p.Thr654Ile) in exon 15, c.1996A>G (p.Met666Val), c.1997T>G (p.Met666Arg), c.1997T>C (p.Met666Thr), c.2011G>A (p.Gly671Arg), and c.2012G>A (p.Gly671Glu) in exon 16. All mutated amino acids were located in the C-terminal proteolytic domain. In available cases, we demonstrated the mutations segregated with the disease. Mutated amino acids are highly conserved, and bioinformatic analysis indicates the substitutions are likely deleterious. This investigation demonstrates that SCA28 accounts for â¼3% of ADCA Caucasian cases negative for triplet expansions and, in extenso, to â¼1.5% of all ADCA. We further confirm both the involvement of AFG3L2 gene in SCA28 and the presence of a mutational hotspot in exons 15-16. Screening for SCA28, is warranted in patients who test negative for more common SCAs and present with a slowly progressive cerebellar ataxia accompanied by oculomotor signs.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ataxia Cerebelar
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Mutação de Sentido Incorreto
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Proteases Dependentes de ATP
Tipo de estudo:
Prevalence_studies
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Risk_factors_studies
Limite:
Adolescent
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Adult
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Aged
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Child
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Child, preschool
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Female
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Humans
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Infant
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Male
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Middle aged
País/Região como assunto:
Europa
Idioma:
En
Revista:
Hum Mutat
Assunto da revista:
GENETICA MEDICA
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Itália