PUBLICATION

A role for the MEGF6 gene in predisposition to osteoporosis

Authors
Teerlink, C.C., Jurynec, M.J., Hernandez, R., Stevens, J., Hughes, D.C., Brunker, C.P., Rowe, K., Grunwald, D.J., Facelli, J.C., Cannon-Albright, L.A.
ID
ZDB-PUB-201008-11
Date
2020
Source
Annals of human genetics   85(2): 58-72 (Journal)
Registered Authors
Grunwald, David, Jurynec, Michael
Keywords
exome sequencing, osteoporosis, pedigree, predisposition, protein folding, zebrafish
MeSH Terms
  • Aged
  • Aged, 80 and over
  • Animals
  • Female
  • Genetic Association Studies*
  • Genetic Predisposition to Disease*
  • Heterozygote
  • Humans
  • Intercellular Signaling Peptides and Proteins/genetics*
  • Male
  • Middle Aged
  • Osteoporosis/genetics*
  • Osteoporosis/pathology
  • Pedigree
  • Phenotype
  • Polymorphism, Single Nucleotide/genetics
  • Whole Exome Sequencing
  • Zebrafish
PubMed
33026655 Full text @ Ann Hum Genet
Abstract
Osteoporosis is a common skeletal disorder characterized by deterioration of bone tissue. The set of genetic factors contributing to osteoporosis is not completely specified. High-risk osteoporosis pedigrees were analyzed to identify genes that may confer susceptibility to disease. Candidate predisposition variants were identified initially by whole exome sequencing of affected-relative pairs, approximately cousins, from 10 pedigrees. Variants were filtered on the basis of population frequency, concordance between pairs of cousins, affecting a gene associated with osteoporosis, and likelihood to have functionally damaging, pathogenic consequences. Subsequently, variants were tested for segregation in 68 additional relatives of the index carriers. A rare variant in MEGF6 (rs755467862) showed strong evidence of segregation with the disease phenotype. Predicted protein folding indicated the variant (Cys200Tyr) may disrupt structure of an EGF-like calcium-binding domain of MEGF6. Functional analyses demonstrated that complete loss of the paralogous genes megf6a and megf6b in zebrafish resulted in significant delay of cartilage and bone formation. Segregation analyses, in silico protein structure modeling, and functional assays support a role for MEGF6 in predisposition to osteoporosis.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes