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

Abstract

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 threedimensional 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 nonconservative 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.

Metaphyseal dysplasia, Spahr type: a mimicker of rickets

“…MDST (OMIM # 250400) was recognised as early as in 1961; however, its molecular basis has been discovered relatively recently in 2014 3. Only a few cases of this disorder have been described in literature.…”

Prenatal course of metaphyseal anadysplasia associated with homozygous mutation in MMP9 identified by exome sequencing

“…A clinically similar but more severe type (MANDP type 1) shows autosomal‐dominant inheritance and is caused by mutations in matrix metalloproteinase type 13 gene ( MMP13 ) . A third condition caused by recessive mutation in MMP13 (metaphyseal dysplasia—Spahr type) also exist . Here, we report the prenatal and postnatal presentation of two pregnancies in one family, affected with MMP9 ‐associated MANDP identified by exome sequencing.…”

“…2 A third condition caused by recessive mutation in MMP13 (metaphyseal dysplasia-Spahr type) also exist. 3 Here, we report the prenatal and postnatal presentation of two pregnancies in one family, affected with MMP9-associated MANDP identified by exome sequencing. At the first encounter she was at week 15 of her third pregnancy.…”

Metalloproteinases and their inhibitors in the pathophysiology of heritable connective tissue disorders: current evidence

“…21 The autosomal dominant form of MAD (MANDP1 [MIM 602111]) is caused by heterozygous mutations in gene MMP-13. 22 MMP-9 and MMP-13 are both involved in the degradation of ECM in the context of bone development.…”