ZFIN ID: ZDB-PUB-190601-19
Functional variants of hepatocyte growth factor identified in patients with adolescent idiopathic scoliosis
Meng, Y., Ma, J., Lin, T., Jiang, H., Wang, C., Yang, F., Zhou, X.
Date: 2019
Source: Journal of cellular biochemistry   120(10): 18236-18245 (Journal)
Registered Authors: Ma, Jun
Keywords: adolescent idiopathic scoliosis, autosomal dominant inheritance, hepatocyte growth factor, whole-genome sequencing
MeSH Terms:
  • Adolescent
  • Animals
  • Asian Continental Ancestry Group/genetics
  • Base Sequence
  • Body Patterning/genetics
  • China
  • Embryo, Nonmammalian/embryology
  • Embryo, Nonmammalian/metabolism
  • Female
  • Gene Knockdown Techniques
  • Genetic Predisposition to Disease/ethnology
  • Genetic Predisposition to Disease/genetics*
  • HEK293 Cells
  • Hepatocyte Growth Factor/genetics*
  • Humans
  • Male
  • Mutation, Missense*
  • Pedigree
  • Scoliosis/ethnology
  • Scoliosis/genetics*
  • Whole Genome Sequencing/methods
  • Zebrafish/embryology
  • Zebrafish/genetics
PubMed: 31148267 Full text @ J. Cell. Biochem.
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.