Germline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformations.
Nat Genet
; 49(4): 613-617, 2017 Apr.
Article
em En
| MEDLINE
| ID: mdl-28288113
ABSTRACT
ABL1 is a proto-oncogene well known as part of the fusion gene BCR-ABL1 in the Philadelphia chromosome of leukemia cancer cells. Inherited germline ABL1 changes have not been associated with genetic disorders. Here we report ABL1 germline variants cosegregating with an autosomal dominant disorder characterized by congenital heart disease, skeletal abnormalities, and failure to thrive. The variant c.734A>G (p.Tyr245Cys) was found to occur de novo or cosegregate with disease in five individuals (families 1-3). Additionally, a de novo c.1066G>A (p.Ala356Thr) variant was identified in a sixth individual (family 4). We overexpressed the mutant constructs in HEK 293T cells and observed increased tyrosine phosphorylation, suggesting increased ABL1 kinase activities associated with both the p.Tyr245Cys and p.Ala356Thr substitutions. Our clinical and experimental findings, together with previously reported teratogenic effects of selective BCR-ABL inhibitors in humans and developmental defects in Abl1 knockout mice, suggest that ABL1 has an important role during organismal development.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Anormalidades Múltiplas
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Doenças do Desenvolvimento Ósseo
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Leucemia Mielogênica Crônica BCR-ABL Positiva
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Transtornos da Alimentação e da Ingestão de Alimentos
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Proteínas de Fusão bcr-abl
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Deformidades Congênitas dos Membros
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Mutação em Linhagem Germinativa
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Anormalidades Craniofaciais
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Transtornos Cromossômicos
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Cardiopatias Congênitas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Nat Genet
Ano de publicação:
2017
Tipo de documento:
Article