ZFIN ID: ZDB-PUB-180328-5
Loss-of-function mutations in FGF8 can be independent risk factors for holoprosencephaly
Hong, S., Hu, P., Roessler, E., Hu, T., Muenke, M.
Date: 2018
Source: Human molecular genetics   27(11): 1989-1998 (Journal)
Registered Authors: Hong, Sung-Kook
Keywords: none
MeSH Terms:
  • Alternative Splicing/genetics*
  • Animals
  • Fibroblast Growth Factor 8/genetics*
  • Fibroblast Growth Factors/genetics*
  • Gene Expression Regulation, Developmental
  • Genetic Predisposition to Disease
  • Hedgehog Proteins/genetics
  • Holoprosencephaly/genetics*
  • Holoprosencephaly/physiopathology
  • Humans
  • In Situ Hybridization
  • Mutation/genetics
  • Risk Factors
  • Signal Transduction/genetics
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics*
PubMed: 29584859 Full text @ Hum. Mol. Genet.
ABSTRACT
The utilization of next generation sequencing has been shown to accelerate gene discovery in human disease. However, our confidence in the correct disease-associations of rare variants continues to depend on functional analysis. Here we employ a sensitive assay of human FGF8 variants in zebrafish to demonstrate that the spectrum of isoforms of FGF8 produced by alternative splicing can provide key insights into the genetic susceptibility to human malformations. In addition, we describe novel mutations in the FGF core structure that have both subtle and profound effects on ligand post-translational processing and biological activity. Finally, we solve a case of apparent digenic inheritance of novel variants in SHH and FGF8, two genes known to functionally co-regulate each other in the developing forebrain, as a simpler case of FGF8 diminished function.
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