title: Mutations in MMP9 and MMP13 determine the mode of inheritance and the clinical spectrum of metaphyseal anadysplasia.
abstract: The matrix metalloproteinases MMP9 and MMP13 catalyze the degradation of extracellular matrix (ECM) components in the growth plate and at the same time cleave and release biologically active molecules stored in the ECM, such as VEGFA. In mice, ablation of Mmp9, Mmp13, or both Mmp9 and Mmp13 causes severe distortion of the metaphyseal growth plate. We report that mutations in either MMP9 or MMP13 are responsible for the human disease metaphyseal anadysplasia (MAD), a heterogeneous group of disorders for which a milder recessive variant and a more severe dominant variant are known. We found that recessive MAD is caused by homozygous loss of function of either MMP9 or MMP13, whereas dominant MAD is associated with missense mutations in the prodomain of MMP13 that determine autoactivation of MMP13 and intracellular degradation of both MMP13 and MMP9, resulting in a double enzymatic deficiency.
authors.affiliation: Centre for Pediatrics and Adolescent Medicine, Freiburg University Hospital, Freiburg, Germany. ekkehart.lausch@uniklinik-freiburg.de
authors.forename: Ekkehart
authors.initials: E
authors.lastname: Lausch
authors.forename: Romy
authors.initials: R
authors.lastname: Keppler
authors.forename: Katja
authors.initials: K
authors.lastname: Hilbert
authors.forename: Valerie
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: Sarah
authors.initials: S
authors.lastname: Nikkel
authors.forename: Gen
authors.initials: G
authors.lastname: Nishimura
authors.forename: Sheila
authors.initials: S
authors.lastname: Unger
authors.forename: Jürgen
authors.initials: J
authors.lastname: Spranger
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: Bernhard
authors.initials: B
authors.lastname: Zabel
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D044466:Asian People / Q000235:genetics / Q000706:statistics & numerical data; D001483:Base Sequence; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D017364:Collagenases / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D053509:Matrix Metalloproteinase 13 / Q000235:genetics* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D041681:NIH 3T3 Cells; D010009:Osteochondrodysplasias / Q000000981:diagnostic imaging / Q000235:genetics*; D010375:Pedigree; D011859:Radiography; D012867:Skin / Q000166:cytology; D055815:Young Adult
chemical_list: D017364:Collagenases; D053509:Matrix Metalloproteinase 13; D020780:Matrix Metalloproteinase 9