title: Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly is caused by a duplication in RUNX2.
abstract: Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is an autosomal-dominant bone dysplasia characterized by metaphyseal flaring of long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, variable brachydactyly, and dystrophic teeth. We performed genome-wide SNP genotyping in five affected and four unaffected members of an extended family with MDMHB. Analysis for copy-number variations revealed that a 105 kb duplication within RUNX2 segregated with the MDMHB phenotype in a region with maximum linkage. Real-time PCR for copy-number variation in genomic DNA in eight samples, as well as sequence analysis of fibroblast cDNA from one subject with MDMHB confirmed that affected family members were heterozygous for the presence of an intragenic duplication encompassing exons 3 to 5 of RUNX2. These three exons code for the Q/A domain and the functionally essential DNA-binding runt domain of RUNX2. Transfection studies with murine Runx2 cDNA showed that cellular levels of mutated RUNX2 were markedly higher than those of wild-type RUNX2, suggesting that the RUNX2 duplication found in individuals with MDMHB leads to a gain of function. Until now, only loss-of-function mutations have been detected in RUNX2; the present report associates an apparent gain-of-function alteration of RUNX2 function with a distinct rare disease.
authors.affiliation: Genetics Unit, Shriners Hospital for Children, Montréal, QC, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Moffatt
authors.forename: Mouna
authors.initials: M
authors.lastname: Ben Amor
authors.forename: Francis H
authors.initials: FH
authors.lastname: Glorieux
authors.forename: Paul
authors.initials: P
authors.lastname: Roschger
authors.forename: Klaus
authors.initials: K
authors.lastname: Klaushofer
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Schwartzentruber
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Paterson
authors.forename: Pingzhao
authors.initials: P
authors.lastname: Hu
authors.forename: Christian
authors.initials: C
authors.lastname: Marshall
authors.forename: Somayyeh
authors.initials: S
authors.lastname: Fahiminiya
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Chandree L
authors.initials: CL
authors.lastname: Beaulieu
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.forename: Frank
authors.initials: F
authors.lastname: Rauch
mesh_terms: D000293:Adolescent; D059327:Brachydactyly / Q000000981:diagnostic imaging / Q000235:genetics*; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics*; D005091:Exons / Q000235:genetics; D019066:Facies; D005190:Family; D005260:Female; D005385:Fingers / Q000002:abnormalities / Q000000981:diagnostic imaging; D020440:Gene Duplication / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D008297:Male; D008437:Maxilla / Q000002:abnormalities / Q000000981:diagnostic imaging; D010009:Osteochondrodysplasias / Q000000981:diagnostic imaging / Q000235:genetics*; D010375:Pedigree; D011859:Radiography; D055815:Young Adult
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C493709:RUNX2 protein, human