Abstract
Osteogenesis imperfecta (OI) is a heritable connective tissue disorder with a predominately autosomal-dominant inheritance pattern. Recessive forms of OI are rare and involve many different causative genes. WNT1 mutations were found to cause either autosomal-recessive OI or dominantly inherited early-onset osteoporosis. Here we describe a 32-year-old boy with severe osteopenia and deformity of the extremities. The relative long thumb and ring finger are obvious. We identified a novel combination of complex heterozygous WNT1 mutation of c.397 A>T (p.Ala133Thr) and c.506dupG (p.Cys170Leufs*) in the proband, both parents and young brother were shown to be heterozygous asymptomatic carriers of the mutation. This is the eleventh family and the thirteenth patient we have ever found in China. Mutation of c.397 A>T (p.Ala133Thr) was found for the third time following our previous findings in two individual families with four patients in total, and may be a hotspot mutation in Chinese WNT1-related OI patients. In silico programs supported the damaging effects for both mutations. The three-D structure demonstrated the severely destroyed stability of WNT1. Serum levels of WNT1, LRP5, and β-catenin were decreased, while higher levels of GSK-3β were detected. The molecular mechanisms of the complex heterozygous mutations need further study.