The gain-of-function FAM83H mutation caused hypocalcification amelogenesis imperfecta in a Chinese family
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ORIGINAL ARTICLE
The gain-of-function FAM83H mutation caused hypocalcification amelogenesis imperfecta in a Chinese family Yingchun Zheng 1 & Ting Lu 2,3 & Jianfan Chen 1 & Meiyi Li 1 & Jun Xiong 4 & Fei He 1 & Zhongzhi Gan 1 & Yingying Guo 1 & Leitao Zhang 2 & Fu Xiong 1,5 Received: 13 March 2020 / Accepted: 28 September 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Objectives Autosomal-dominant hypocalcification amelogenesis imperfecta (ADHCAI) is a hereditary disease characterized by enamel defects. ADHCAI is mainly caused by nonsense mutations in a gene called family with sequence similarity 83 member H (FAM83H). To study the pathogenesis of ADHCAI, a Chinese ADHCAI family was investigated. Materials and methods The ultrastructure of enamel was analyzed by micro-CT and scanning electron microscopy. Wholeexome sequencing (WES) was performed to identify the pathogenic gene. The function of the mutant FAM83H was studied by real-time PCR, western blotting, subcellular localization, and protein degradation pathway analyses. Results WES identified a known nonsense mutation (c.1915A > T) in exon 5 of the FAM83H gene, causing a truncated protein (p.Lys639*). However, the cases reported herein exhibited significant differences in the clinical phenotype compared with that the previously reported case. An abnormal enamel rod head structure was observed in affected teeth. In vitro functional studies showed altered protein localization and a decreased protein degradation rate for mutant FAM83H. Conclusions We verified the FAM83H p.Lys639* protein as a gain-of-function variant causing ADHCAI. Abnormal enamel rod head structure was observed in teeth with mutant FAM83H proteins. We also investigated the molecular pathogenesis and presented data on the abnormal degradation of mutant FAM83H proteins. Clinical relevance This study helped the family members to understand the disease progression and provided new insights into the pathogenesis of ADHCAI. Due to the large heterogeneity of ADHCAI, this study also provided a genetic basis for individuals who exhibit similar clinical phenotypes. Keywords ADHCAI . Whole-exome sequencing . FAM83H . Protein degradation
Yingchun Zheng and Ting Lu contributed equally to this work. * Leitao Zhang [email protected] * Fu Xiong [email protected] 1
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
2
Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
3
College of Stomatology, Southern Medical University, Guangzhou, Guangdong, China
4
Department of Laboratory Medicine, ZhuJiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
5
Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Guangzhou, Guangdong, China
Introduction Amelogenesis imperfecta (AI) is a hereditary nonsyndromic disease that affects enamel formation or mineralization which leads to enamel defects. AI affects the structure, a
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