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The gain-of-function FAM83H mutation caused hypocalcification amelogenesis imperfecta in a Chinese family

Clinical Oral Investigations volume 25, pages 2915–2923 (2021)Cite this article

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. Whole-exome 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.

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Funding

We thank the patients and their family members for consenting to this research. This work was supported mainly by a grant from the National Natural Science Foundation of China (31970558), the Natural Science Foundation of Guangdong Province (2018B030311033), the Science and Technology Planning Project of Guangdong Province (2019A030317019), and the President Foundation of Nanfang Hospital, Southern Medical University (2018C021).

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Author notes

  1. Yingchun Zheng and Ting Lu contributed equally to this work.

Affiliations

  1. Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China

    Yingchun Zheng, Jianfan Chen, Meiyi Li, Fei He, Zhongzhi Gan, Yingying Guo & Fu Xiong

  2. Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China

    Ting Lu & Leitao Zhang

  3. College of Stomatology, Southern Medical University, Guangzhou, Guangdong, China

    Ting Lu

  4. Department of Laboratory Medicine, ZhuJiang Hospital, Southern Medical University, Guangzhou, Guangdong, China

    Jun Xiong

  5. Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Guangzhou, Guangdong, China

    Fu Xiong

Authors
  1. Yingchun Zheng
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  2. Ting Lu
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Contributions

Fu Xiong and Leitao Zhang contributed to the study conception and design. Material preparation was performed by Ting Lu and Leitao Zhang. Data collection and analysis were performed by Yingchun Zheng, Jianfan Chen, Meiyi Li, Fei He, and Zhongzhi Gan. Bioinformatics and statistical analyses were performed by Jun Xiong and Yingying Guo. The first draft of the manuscript was written by Yingchun Zheng and Fu Xiong. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Leitao Zhang or Fu Xiong.

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The authors declare that they have no conflict of interest.

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Approval was obtained from the Ethics Committee of Nanfang Hospital, an affiliate of Southern Medical University. The procedures used in this study adhere to the tenets of the Declaration of Helsinki.

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Written informed consent was obtained from all participants or their guardians.

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Zheng, Y., Lu, T., Chen, J. et al. The gain-of-function FAM83H mutation caused hypocalcification amelogenesis imperfecta in a Chinese family. Clin Oral Invest 25, 2915–2923 (2021). https://doi.org/10.1007/s00784-020-03609-6

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  • DOI: https://doi.org/10.1007/s00784-020-03609-6

Keywords

  • ADHCAI
  • Whole-exome sequencing
  • FAM83H
  • Protein degradation