Deficiency for the ER-stress transducer OASIS causes severe recessive osteogenesis imperfecta in humans

Hulya Kayserili,Sofie Symoens,Paul J Coucke,Anne De Paepe,Annelies Dheedene,Hans Peter Bächinger,Sanne D’Hondt,Fransiska Malfait,Wouter Steyaert,Bert Callewaert

doi:10.1186/1750-1172-8-154

Abstract

Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous brittle bone disorder. Whereas dominant OI is mostly due to heterozygous mutations in either COL1A1 or COL1A2, encoding type I procollagen, recessive OI is caused by biallelic mutations in genes encoding proteins involved in type I procollagen processing or chaperoning. Hitherto, some OI cases remain molecularly unexplained. We detected a homozygous genomic deletion of CREB3L1 in a family with severe OI. CREB3L1 encodes OASIS, an endoplasmic reticulum-stress transducer that regulates type I procollagen expression during murine bone formation. This is the first report linking CREB3L1 to human recessive OI, thereby expanding the OI gene spectrum.

Highlights

Osteogenesis imperfecta (OI) is a genetically heterogeneous brittle bone disorder with varying degrees of clinical severity, ranging from perinatal lethality to generalized osteopenia [1]
The predominant autosomal dominant forms display mutations in either COL1A1 or COL1A2, encoding the α1- and α2-chains of type I procollagen, while rarer autosomal recessive forms mostly result from defective endoplasmic reticulum (ER)-resident proteins involved in post-translational processing or chaperoning of these α(I)-chains [1,2]
A recurrent mutation in a gene encoding the Interferon-inducible transmembrane protein 5 (IFITM5), which is involved in bone growth during prenatal murine development, was recently shown to cause autosomal (AD) dominant OI [19,20,21]

Summary

Introduction

Osteogenesis imperfecta (OI) is a genetically heterogeneous brittle bone disorder with varying degrees of clinical severity, ranging from perinatal lethality to generalized osteopenia [1]. A recurrent mutation in a gene encoding the Interferon-inducible transmembrane protein 5 (IFITM5), which is involved in bone growth during prenatal murine development, was recently shown to cause autosomal (AD) dominant OI [19,20,21]. Heterozygous and homozygous mutations in WNT1 (WNT1), which is a key signalling molecule in osteoblast function and bone development, were shown to underlie certain forms of AD early-onset osteoporosis and AR OI, which was in some patients associated with severe intellectual disability [22,23,24,25,26].

Results

Conclusion