A Novel FAM83H Truncation Mutation Disrupts Enamel Mineralization in Autosomal Dominant Hypocalcified Amelogenesis...

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.

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).

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.

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.