FAM83H mutations in families with autosomal-dominant hypocalcified amelogenesis imperfecta

Abstract

Amelogenesis imperfecta (AI) is a collection of diverse inherited disorders featuring dental-enamel defects in the absence of significant nondental symptoms. AI phenotypes vary and are categorized as hypoplastic, hypocalcified, and hypomaturation types. Phenotypic specificity to enamel has focused research on genes encoding enamel-matrix proteins. We studied two families with autosomal-dominant hypocalcified AI and have identified nonsense mutations (R325X and Q398X) in the FAM83H gene on chromosome 8q24.3. The mutations perfectly cosegregate with the disease phenotype and demonstrate that FAM83H is required for proper dental-enamel calcification.

Figure 1

Pedigree and Haplotype of the ADHCAI Family 1 Affected individuals are indicated by black symbols including the proband (V:11). Squares represent males, and circles represent females. Bars shown below each individual indicate the genotypes of the microsatellite markers. The black bar represents the marker haplotype that segregates with the affected status. Microsatellite markers are shown in their chromosomal order.

Figure 2

Mutations in FAM83H (A) Clinical photograph (upper) and panoramic radiograph (lower) of an affected individual in the ADHCAI family 2. (B) The DNA sequence of a segment of FAM83H exon 5 for R325X (left) and Q398X (right) mutation of patients and wild-type sequence (Wt). Nucleotide sequences and corresponding amino acids are shown below each chromatogram. The positions of nucleotide changes are marked by black arrows. (C) Gene structure of FAM83H. Five exons (box) and introns (line) were drawn (upper). The number of each exon is shown below the gene structure. The position of each mutation is marked by black lines above the gene structure. Darkened boxes represent coding regions. Normal and mutated protein structure were drawn (below)

Figure 3

In Situ Hybridization and RT-PCR (A) Expression of AA3409316, mouse homolog of human FAM83H, was detected by DIG labeled antisense RNA probe. Expression in the ameloblast (arrowhead) and odontoblast (arrow) can be seen in the anterior tooth of a 3-week-old mouse mandible. (B) RT-PCR analysis shows that FAM83H is expressed in the ameloblast and odontoblast. AA3409316 expression was detected in the mouse eye, liver, and kidney (+, reactions with reverse transcriptase; −, reactions without reverse transcriptase).