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The role of WNT1 mutant variant (WNT1 c.677C>T ) in osteogenesis imperfecta
Annals of Human Genetics ( IF 1.9 ) Pub Date : 2020-08-05 , DOI: 10.1111/ahg.12399 Bashan Zhang 1 , Rong Li 1 , Wenfeng Wang 1 , Xueming Zhou 2 , Beijing Luo 1 , Zinian Zhu 1 , Xibo Zhang 1 , Aijiao Ding 1
Annals of Human Genetics ( IF 1.9 ) Pub Date : 2020-08-05 , DOI: 10.1111/ahg.12399 Bashan Zhang 1 , Rong Li 1 , Wenfeng Wang 1 , Xueming Zhou 2 , Beijing Luo 1 , Zinian Zhu 1 , Xibo Zhang 1 , Aijiao Ding 1
Affiliation
Osteogenesis imperfecta (OI), also known as “brittle bone disease,” is a rare inherited genetic disorder characterized by bone fragility and often associated with short stature. The mutation in WNT1 causes autosomal recessive OI (AR‐OI) due to the key role of WNT/β‐catenin signaling in bone formation. WNT1 mutations cause phenotypes in OI of varying degrees of clinical severity, ranging from moderate to progressively deforming forms. The nucleotide change c.677C > T is one of the recurrent variants in the WNT1 alleles in Chinese AR‐OI patients. To explore the effects of mutation c.677C > T on WNT1 function, we evaluated the activation of WNT/β‐catenin signaling, cell proliferation, osteoblast differentiation, and osteoclast differentiation in WNT1c.677C>T, WNT1c.884C>A, and wild type WNT1 transfected into MC3T3‐E1 preosteoblasts. Plasmids containing wild type WNT1, WNT1c.677C>T, and WNT1c.884C>A cDNAs were constructed. Protein levels of phosphorylation at serine 9 of GSK‐3β (p‐GSK‐3β), GSK‐3β, nonphosphorylated β‐catenin (non‐p‐β‐catenin), and β‐catenin were detected with western blot. Cell proliferation was determined using MTS. BMP‐2 and RANKL mRNA and protein levels were detected by qPCR and western blot. Our results showed that WNT1c.677C>T failed to activate WNT/β‐catenin signaling and impaired the proliferation of preosteoblasts. Moreover, compared to wild type WNT1, WNT1c.677C>T downregulated BMP‐2 protein expression and was exhibited a diminished capacity to suppress the RANKL protein level. In conclusion, mutation c.677C > T hindered the ability of WNT1 to induce the WNT/β‐catenin signaling pathway and it affected the WNT/β‐catenin pathway which might potentially contribute to hampered bone homeostasis.
更新日期：2020-08-05
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