Abstract:
:Osteogenesis imperfecta (OI) is a heritable disorder that ranges in severity from death in the perinatal period to an increased lifetime risk of fracture. Mutations in COL1A1 and COL1A2, which encode the chains of type I procollagen, result in dominant forms of OI, and mutations in several other genes result in recessive forms of OI. Here, we describe four recessive-OI-affected families in which we identified causative mutations in wingless-type MMTV integration site family 1 (WNT1). In family 1, we identified a homozygous missense mutation by exome sequencing. In family 2, we identified a homozygous nonsense mutation predicted to produce truncated WNT1. In family 3, we found a nonsense mutation and a single-nucleotide duplication on different alleles, and in family 4, we found a homozygous 14 bp deletion. The mutations in families 3 and 4 are predicted to result in nonsense-mediated mRNA decay and the absence of WNT1. WNT1 is a secreted signaling protein that binds the frizzled receptor (FZD) and the coreceptor low-density lipoprotein-receptor-related protein 5 (LRP5). Biallelic loss-of-function mutations in LRP5 result in recessive osteoporosis-pseudoglioma syndrome with low bone mass, whereas heterozygous gain-of-function mutations result in van Buchem disease with elevated bone density. Biallelic loss-of-function mutations in WNT1 result in a recessive clinical picture that includes bone fragility with a moderately severe and progressive presentation that is not easily distinguished from dominant OI type III.
journal_name
Am J Hum Genetjournal_title
American journal of human geneticsauthors
Pyott SM,Tran TT,Leistritz DF,Pepin MG,Mendelsohn NJ,Temme RT,Fernandez BA,Elsayed SM,Elsobky E,Verma I,Nair S,Turner EH,Smith JD,Jarvik GP,Byers PHdoi
10.1016/j.ajhg.2013.02.009subject
Has Abstractpub_date
2013-04-04 00:00:00pages
590-7issue
4eissn
0002-9297issn
1537-6605pii
S0002-9297(13)00081-5journal_volume
92pub_type
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