Rare coding variants in MAPK7 predispose to adolescent idiopathic scoliosis

Hum Mutat. 2017 Nov;38(11):1500-1510. doi: 10.1002/humu.23296. Epub 2017 Jul 25.

Abstract

Adolescent idiopathic scoliosis (AIS) is a complex genetic disorder characterized by three-dimensional spinal curvatures, affecting 2%-3% of school age children, yet the causes underlying AIS are not well understood. Here, we first conducted a whole-exome sequencing and linkage analysis on a three-generation Chinese family with autosomal-dominant (AD) AIS, and then performed targeted sequencing in a discovery cohort comprising 20 AD AIS families and 86 simplex patients, and finally identified three disease-associated missense variants (c.886G> A, c.1943C> T, and c.1760C> T) in the MAPK7 gene (encoding mitogen-activated protein kinase 7). Genotyping of the three rare variants in a Chinese replication cohort comprising 1,038 simplex patients and 1,841 controls showed that their combined allele frequency was significantly over-represented in patients as compared with controls (2.0% [41/2,076] vs. 0.7% [27/3,682]; odds ratio = 2.7; P = 2.8 × 10-5 ). In vitro, we demonstrated that the three MAPK7 mutants disrupted nuclear translocation in cellular models, which is necessary for the normal function of MAPK7. In vivo, we also conducted CRISPR/Cas9-mediated deletion of mapk7 in zebrafish recapitulating the characteristic phenotype of idiopathic scoliosis. Taken together, our findings suggest that rare coding variants in MAPK7 predispose to AIS, providing clues to understanding the mechanisms of AIS.

Keywords: CRISPR/Cas9; MAPK7; adolescent idiopathic scoliosis; whole-exome sequencing; zebrafish.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Alleles
  • Animals
  • Child
  • Disease Models, Animal
  • Female
  • Gene Frequency
  • Gene Targeting
  • Genetic Association Studies*
  • Genetic Linkage
  • Genetic Predisposition to Disease*
  • Genetic Variation*
  • Genotype
  • Humans
  • Male
  • Mitogen-Activated Protein Kinase 7 / chemistry
  • Mitogen-Activated Protein Kinase 7 / genetics*
  • Mutation
  • Open Reading Frames*
  • Phenotype
  • Radiography
  • Scoliosis / diagnosis*
  • Scoliosis / genetics*
  • Scoliosis / surgery
  • Structure-Activity Relationship
  • Whole Exome Sequencing
  • Zebrafish

Substances

  • MAPK7 protein, human
  • Mitogen-Activated Protein Kinase 7