Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis

Nat Genet. 2011 Mar 6;43(4):306-8. doi: 10.1038/ng.778.

Abstract

Hajdu-Cheney syndrome is a rare autosomal dominant skeletal disorder with facial anomalies, osteoporosis and acro-osteolysis. We sequenced the exomes of six unrelated individuals with this syndrome and identified heterozygous nonsense and frameshift mutations in NOTCH2 in five of them. All mutations cluster to the last coding exon of the gene, suggesting that the mutant mRNA products escape nonsense-mediated decay and that the resulting truncated NOTCH2 proteins act in a gain-of-function manner.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Base Sequence
  • Child, Preschool
  • Codon, Nonsense
  • DNA / genetics
  • Exons
  • Female
  • Frameshift Mutation
  • Hajdu-Cheney Syndrome / genetics*
  • Hajdu-Cheney Syndrome / metabolism
  • Hajdu-Cheney Syndrome / pathology
  • Heterozygote
  • Humans
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • Rare Diseases / genetics
  • Rare Diseases / metabolism
  • Rare Diseases / pathology
  • Receptor, Notch2 / genetics*
  • Receptor, Notch2 / metabolism
  • Signal Transduction
  • Young Adult

Substances

  • Codon, Nonsense
  • NOTCH2 protein, human
  • Receptor, Notch2
  • DNA

Associated data

  • RefSeq/NM_024408
  • RefSeq/NP_077719