title: 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 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.
authors.affiliation: Division of Molecular Pediatrics, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Luisa
authors.initials: L
authors.lastname: Bonafé
authors.forename: Jinlong
authors.initials: J
authors.lastname: Liang
authors.forename: Maria W
authors.initials: MW
authors.lastname: Gorna
authors.forename: Qingyan
authors.initials: Q
authors.lastname: Zhang
authors.forename: Russia
authors.initials: R
authors.lastname: Ha-Vinh
authors.forename: Ana Belinda
authors.initials: AB
authors.lastname: Campos-Xavier
authors.forename: Sheila
authors.initials: S
authors.lastname: Unger
authors.forename: Jacques S
authors.initials: JS
authors.lastname: Beckmann
authors.forename: Antony
authors.initials: A
authors.lastname: Le Béchec
authors.forename: Brian
authors.initials: B
authors.lastname: Stevenson
authors.forename: Andres
authors.initials: A
authors.lastname: Giedion
authors.forename: Xuanzhu
authors.initials: X
authors.lastname: Liu
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: André
authors.initials: A
authors.lastname: Spahr
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D020134:Catalytic Domain; D002648:Child; D024161:Collagen Type XI / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D005808:Genes, Recessive; D005838:Genotype; D006197:Hair / Q000002:abnormalities*; D006627:Hirschsprung Disease / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000737:chemistry / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation; D010009:Osteochondrodysplasias / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics; D010375:Pedigree; D000081207:Primary Immunodeficiency Diseases; D011487:Protein Conformation; D062085:RNA, Long Noncoding / Q000235:genetics; D055815:Young Adult
chemical_list: C574182:COL11A1 protein, human; D024161:Collagen Type XI; C544035:RMRP non-coding RNA, human; D062085:RNA, Long Noncoding; D053509:Matrix Metalloproteinase 13
keywords: MMP13; Spahr dysplasia; exome sequencing; metalloproteinase; metaphyseal dysplasia