Mutational analysis of X-linked amelogenesis imperfecta in multiple families

Seven mutations in the amelogenin gene are associated with X-linked amelogenesis imperfecta. These mutations can produce reductions in the amount of enamel and the degree of mineralization. Two families have been identified from western North Carolina exhibiting features of amelogenesis imperfecta, characterized by brown enamel in affected males and interposed vertical bands of normal appearing and brown enamel in presumably heterozygous females. Mutational analysis reveals a C-A mutation in exon 6 at codon 41 of the X-chromosomal amelogenin gene, resulting in a pro-thr change in all individuals having the amelogenesis imperfecta phenotype. This mutation was previously reported in a family with X-linked hypomaturation amelogenesis imperfecta. There is no known relationship between any of the three families but the presence of similar phenotypes and common mutations suggests they may be distantly related. For individuals from all three families, the haplotype for six highly polymorphic loci flanking the amelogenin gene was determined. A common haplotype was demonstrated among two of the three families, suggesting that the mutation may have been inherited from a common ancestor. The finding that the third family had a distinct haplotype may indicate that the C-A mutation at codon 41 represents a mutational hotspot that occurs with greater frequency than other known amelogenin gene mutations. The phenotype resulting from this mutation was highly consistent in affected male members of the same family and between families.