Functional variants of hepatocyte growth factor identified in patients with adolescent idiopathic scoliosis.
J Cell Biochem
; 120(10): 18236-18245, 2019 10.
Article
em En
| MEDLINE
| ID: mdl-31148267
ABSTRACT
The genetic etiology of adolescent idiopathic scoliosis (AIS) remains obscure. Whole-genome sequencing was performed in four members of one family. Then, we performed a rigorous computational analysis to determine the deleterious effects of the identified variants. Furthermore, the structural differences between the native hepatocyte growth factor (HGF) protein and a protein encoded by an HGF variant containing one mutation (p.T596M) were analyzed using molecular dynamic stimulation. A novel heterozygous mutation (p.T596M) within the HGF gene was identified and found to cosegregate with scoliosis phenotypes in three affected family members. Subsequent modeling and structure-based analyses supported the theory that this mutation is functionally deleterious. Functional analyses demonstrated that the HGF p.T596 M mutation changed the ability of the HGF protein to be secreted and impaired migration and invasion in HEK293T cells. Furthermore, an HGF knockdown zebrafish model exhibited a curly tailed phenotype. Mutation in HGF is associated with an autosomal dominant pattern of inheritance of AIS. This finding increases our understanding of the genetic heterogeneity of AIS.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Escoliose
/
Fator de Crescimento de Hepatócito
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Predisposição Genética para Doença
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Mutação de Sentido Incorreto
Tipo de estudo:
Prognostic_studies
Limite:
Adolescent
/
Animals
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Female
/
Humans
/
Male
País/Região como assunto:
Asia
Idioma:
En
Revista:
J Cell Biochem
Ano de publicação:
2019
Tipo de documento:
Article