MMP13 mutations are the cause of recessive metaphyseal dysplasia, Spahr type

Am J Med Genet A. 2014 May;164A(5):1175-9. doi: 10.1002/ajmg.a.36431. Epub 2014 Mar 19.


Metaphyseal dysplasia, Spahr type (MDST; OMIM 250400) was described in 1961 based on the observation of four children in one family who had rickets-like metaphyseal changes but normal blood chemistry and moderate short stature. Its molecular basis and nosologic status remained unknown. We followed up on those individuals and diagnosed the disorder in an additional member of the family. We used exome sequencing to ascertain the underlying mutation and explored its consequences on three-dimensional models of the affected protein. The MDST phenotype is associated with moderate short stature and knee pain in adults, while extra-skeletal complications are not observed. The sequencing showed that MDST segregated with a c.619T>G single nucleotide transversion in MMP13. The predicted non-conservative amino acid substitution, p.Trp207Gly, disrupts a crucial hydrogen bond in the calcium-binding region of the catalytic domain of the matrix metalloproteinase, MMP13. The MDST phenotype is associated with recessive MMP13 mutations, confirming the importance of this metalloproteinase in the metaphyseal growth plate. Dominant MMP13 mutations have been associated with metaphyseal anadysplasia (OMIM 602111), while a single child homozygous for a MMP13 mutation had been previously diagnosed as "recessive metaphyseal anadysplasia," that we conclude is the same nosologic entity as MDST. Molecular confirmation of MDST allows distinction of it from dominant conditions (e.g., metaphyseal dysplasia, Schmid type; OMIM # 156500) and from more severe multi-system conditions (such as cartilage-hair hypoplasia; OMIM # 250250) and to give precise recurrence risks and prognosis.

Keywords: MMP13; Spahr dysplasia; exome sequencing; metalloproteinase; metaphyseal dysplasia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Catalytic Domain
  • Child
  • Collagen Type XI / genetics
  • Female
  • Follow-Up Studies
  • Genes, Recessive*
  • Genotype
  • Hair / abnormalities*
  • Hirschsprung Disease / diagnosis*
  • Hirschsprung Disease / genetics*
  • Humans
  • Immunologic Deficiency Syndromes / diagnosis*
  • Immunologic Deficiency Syndromes / genetics*
  • Male
  • Matrix Metalloproteinase 13 / chemistry
  • Matrix Metalloproteinase 13 / genetics*
  • Models, Molecular
  • Mutation*
  • Osteochondrodysplasias / congenital*
  • Osteochondrodysplasias / diagnosis
  • Osteochondrodysplasias / genetics
  • Pedigree
  • Primary Immunodeficiency Diseases
  • Protein Conformation
  • RNA, Long Noncoding / genetics
  • Young Adult


  • COL11A1 protein, human
  • Collagen Type XI
  • RMRP non-coding RNA, human
  • RNA, Long Noncoding
  • Matrix Metalloproteinase 13

Supplementary concepts

  • Cartilage-hair hypoplasia