Exome sequencing reveals a nonsense mutation in MMP13 as a new cause of autosomal recessive metaphyseal anadysplasia

Eur J Hum Genet. 2015 Feb;23(2):264-6. doi: 10.1038/ejhg.2014.76. Epub 2014 Apr 30.

Abstract

Metaphyseal anadysplasia (MANDP) is an uncommon chondrodysplasia characterized by early-onset metaphyseal dysplasia and short stature that improves with age. MANDP is caused by mutations in the matrix metalloproteinase (MMP) 9 and 13 genes. Autosomal dominant (AD) MANDP has been described as more severe, and has been associated with dominant-negative MMP13 mutations that suppress activity of both MMP9 and MMP13; autosomal recessive (AR) MANDP has been described as a milder form associated with AR missense mutations in MMP9 or MMP13. Here we describe the molecular characterization of skeletal dysplasia in two brothers who presented with short stature and mixed epiphyseal and metaphyseal dysplasia. Whole-exome sequencing (WES) identified a homozygous C>T transition mutation in exon 2 of MMP13 (c.325C>T) on chromosome 11q22.2 resulting in a premature stop codon p.(R109*) that is predicted to abolish MMP13 activity. This report extends the MANDP phenotype by illustrating that AR nonsense mutations in MMP13 can lead to short stature that persists beyond childhood.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Child
  • Codon, Nonsense*
  • Exons*
  • Genes, Recessive*
  • Humans
  • Limb Deformities, Congenital / diagnosis
  • Limb Deformities, Congenital / genetics*
  • Male
  • Matrix Metalloproteinase 13 / genetics*
  • Osteochondrodysplasias / diagnosis
  • Osteochondrodysplasias / genetics*
  • Siblings

Substances

  • Codon, Nonsense
  • MMP13 protein, human
  • Matrix Metalloproteinase 13

Supplementary concepts

  • Metaphyseal anadysplasia