Novel missense loss-of-function mutations of WNT1 in an autosomal recessive Osteogenesis imperfecta patient

European Journal of Medical Genetics
Joon Yeon WonTae-Joon Cho

Abstract

Osteogenesis imperfecta (OI) is a heritable skeletal disorder characterized by bone fragility and low bone mass. Recently, loss-of-function mutations of WNT1 have been reported to be causative in OI or osteoporosis. We report an OI patient with novel compound heterozygous WNT1 missense mutations, p.Glu123Asp and p.Cys153Gly. Both mutations are found in the exon 3, and the p.Glu123Asp is the most proximal N-terminus missense mutation among the reported WNT1 missense mutations in OI patients. In vitro functional analysis reveals that while expression of wildtype WNT1 stimulates canonical WNT1-mediated β-catenin signaling, that of individual WNT1 mutant fails to do so, indicative of the pathogenic nature of the WNT1 variants. Although the pathogenic mechanism of WNT1 defects in OI has yet to be uncovered, these findings further contribute to the implications and importance of functional relevance of WNT1 in skeletal disorders.

Citations

Mar 22, 2019·American Journal of Medical Genetics. Part a·Sheela NampoothiriFransiska Malfait
Mar 27, 2019·Endocrine Practice : Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists·Yang-Jia CaoZhen-Lin Zhang
Mar 20, 2018·Intractable & Rare Diseases Research·Yanqin LuJinxiang Han
Jan 30, 2019·Journal of Human Genetics·Piranit Nik KantaputraPrapai Dejkhamron

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