Mutational spectrum of FAM83H: the C-terminal portion is required for tooth enamel calcification

Abstract

Dental enamel forms through the concerted activities of specialized extracellular matrix proteins, including amelogenin, enamelin, MMP20, and KLK4. Defects in the genes encoding these proteins cause non-syndromic inherited enamel malformations collectively designated as amelogenesis imperfecta (AI). These genes, however, account for only about a quarter of all AI cases. Recently we identified mutations in FAM83H that caused autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI). Unlike other genes that cause AI, FAM83 H does not encode an extracellular matrix protein. Its location inside the cell is completely unknown, as is its function. We here report novel FAM83H mutations in four kindreds with ADHCAI. All are nonsense mutations in the last exon (c.1243G>T, p.E415X; c.891T>A, p.Y297X; c.1380G>A, p.W460X; and c.2029C>T, p.Q677X). These mutations delete between 503 and 883 amino acids from the C-terminus of a protein normally comprised of 1179 residues. The reason these mutations cause such extreme defects in the enamel layer without affecting other parts of the body is not known yet. However it seems evident that the large C-terminal part of the protein is essential for proper enamel calcification.

Figure 1

A: Pedigree of family 1 (p.E415X). Oral photographs show the proband (IV-4). Upper photo is the mandibular incisors at age 7 years and 11 months. Lower one is a photo at age 10 years and 10 months. B: Pedigree of family 2 (p.Y297X) and oral photograph of proband (II-1). C: Pedigree of family 3 (p.W460X) and oral photograph of proband at age 8. D: Pedigree of family 4 (p.Q677X) with panorex and oral photographs of proband (IV-2) at age 13 years and 5 months.

Figure 2

Gene diagram showing the 5 exons (boxes) and 4 introns (bars) of FAM83H. The non-coding regions in exons are shaded. The number of base pairs (bp) in an intron is shown above the intron. The number of base pairs in an exon is below the exon, followed by the number of amino acid codons in the exon and the range of amino acids encoded by the exon. The disease-causing mutations reported here are marked in bold above exon 5. The disease-causing mutations reported previously are marked in bold below exon 5.