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: Pierre Moffatt, Mouna Ben Amor, Francis H Glorieux, Paul Roschger, Klaus Klaushofer, Jeremy A Schwartzentruber, Andrew D Paterson, Pingzhao Hu, Christian Marshall, FORGE Canada Consortium, Somayyeh Fahiminiya, Jacek Majewski, Chandree L Beaulieu, Kym M Boycott, Frank Rauch
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 92 Issue 2 Pg. 252-8 (Feb 07 2013) ISSN: 1537-6605 [Electronic] United States
• PMID: 23290074 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• Core Binding Factor Alpha 1 Subunit
• RUNX2 protein, human

Topics

• Adolescent
• Brachydactyly (diagnostic imaging, genetics)
• Chromosomes, Human, Pair 6 (genetics)
• Core Binding Factor Alpha 1 Subunit (genetics)
• Exons (genetics)
• Facies
• Family
• Female
• Fingers (abnormalities, diagnostic imaging)
• Gene Duplication (genetics)
• Genome, Human (genetics)
• Humans
• Male
• Maxilla (abnormalities, diagnostic imaging)
• Osteochondrodysplasias (diagnostic imaging, genetics)
• Pedigree
• Radiography
• Young Adult