Title
Identification of biallelic LRRK1 mutations in osteosclerotic metaphyseal dysplasia and evidence for locus heterogeneity Identification of biallelic LRRK1 mutations in osteosclerotic metaphyseal dysplasia and evidence for locus heterogeneity
Author
Faculty/Department
Faculty of Medicine and Health Sciences
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Publication type
article
Publication
London ,
Subject
Human medicine
Source (journal)
Journal of medical genetics. - London
Volume/pages
53(2016) :8 , p. 568-574
ISSN
0022-2593
ISI
000380816700008
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
Background Osteosclerotic metaphyseal dysplasia (OSMD) is a unique form of osteopetrosis characterised by severe osteosclerosis localised to the bone ends. The mode of inheritance is autosomal recessive. Its genetic basis is not known. Objective To identify the disease gene for OSMD. Methods and results By whole exome sequencing in a boy with OSMD, we identified a homozygous 7 bp deletion (c.5938_5944delGAGTGGT) in the LRRK1 gene. His skeletal phenotype recapitulated that seen in the Lrrk1-deficient mouse. The shared skeletal hallmarks included severe sclerosis in the undermodelled metaphyses and epiphyseal margins of the tubular bones, costal ends, vertebral endplates and margins of the flat bones. The deletion is predicted to result in an elongated LRRK1 protein (p.E1980Afs*66) that lacks a part of its WD40 domains. In vitro functional studies using osteoclasts from Lrrk1-deficient mice showed that the deletion was a loss of function mutation. Genetic analysis of LRRK1 in two unrelated patients with OSMD suggested that OSMD is a genetically heterogeneous condition. Conclusions This is the first study to identify the causative gene of OSMD. Our study provides evidence that LRRK1 plays a critical role in the regulation of bone mass in humans.
E-info
https://repository.uantwerpen.be/docman/iruaauth/57018f/133433.pdf
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