A Novel FAM83H Truncation Mutation Disrupts Enamel Mineralization in Autosomal Dominant Hypocalcified Amelogenesis Imperfecta
TL;DR
These findings are consistent with the “presecretory pathogenesis” model for ADHCAI, wherein nuclear‐mislocalized truncated FAM83H may disrupt enamel mineralization partly through transcriptional suppression of matrix components.
Abstract
ABSTRACT Objectives Autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI; OMIM#130900) is a hereditary enamel defect caused by truncation mutations in FAM83H, though the underlying pathogenic mechanisms remain incompletely understood. This study aimed to identify novel FAM83H mutations in a Chinese family with ADHCAI and to investigate their functional consequences on enamel formation. Materials and Methods A three‐generation ADHCAI family underwent clinical and genetic evaluation. Whole‐exome sequencing and Sanger sequencing were used for mutation identification. The proband's enamel was analyzed by scanning electron microscopy with energy‐dispersive X‐ray spectroscopy (SEM‐EDX). Structural impacts of the mutation were predicted bioinformatically (PSIPRED, SWISS‐MODEL). Patient‐derived periodontal ligament cells (PDLCs) were assessed by Western blot, immunofluorescence, and quantitative real‐time PCR for key enamel matrix proteins (AMELX, AMBN, ENAM) and osteogenic markers (RUNX2, ALP). Results A novel heterozygous nonsense mutation (c.1819G>T, p.(Glu607*)) in FAM83H was identified, resulting in a C‐terminally truncated protein lacking 573 residues that mislocalizes from the cytoplasm to the nucleus. SEM‐EDX revealed disorganized enamel ultrastructure, a reduced calcium‐to‐phosphorus ratio, and increased porosity. Functional analysis in PDLCs showed coordinated downregulation of enamel matrix proteins and osteogenic markers, indicating a dual regulatory role for FAM83H in biomineralization. Conclusions Our findings are consistent with the “presecretory pathogenesis” model for ADHCAI, wherein nuclear‐mislocalized truncated FAM83H may disrupt enamel mineralization partly through transcriptional suppression of matrix components. This expands the FAM83H mutational spectrum, offers preliminary mechanistic insight, and suggests potential targets for pre‐eruptive therapeutic strategies.