Recessive COL17A1 Mutations and a Dominant LAMB3 Mutation Cause Hypoplastic Amelogenesis Imperfecta

Abstract

Hereditary conditions that affect tooth enamel in quantity and/or quality are called amelogenesis imperfecta (AI). AI can occur as an isolated condition or as a symptom of a syndrome. An OMIM search with the term "AI" yielded 79 result entries. Mutations in the same gene cause syndromic or non-syndromic AI, depending on the nature of the mutations. In this study, we recruited two AI families and performed mutational analysis using whole-exome sequencing. The proband of family 1, with hypoplastic pitted AI and mild localized atopic dermatitis, had compound heterozygous COL17A1 mutations (paternal NM_000494.4: c.3598G>T, p.Asp1200Tyr and maternal c.1700G>A, p.Gly567Glu). The proband of family 2, with hypoplastic pitted AI and Jervell and Lange-Nielsen syndrome, had a recurrent LAMB3 mutation (NM_000228.3: c.3463_3475del, p.(Glu1155Thrfs*51)) in addition to compound heterozygous mutations in the KCNQ1 gene.

Keywords: COL17A1; LAMB3; enamel defects; hereditary; mutation.

Figure 1

Pedigree, clinical photos, and panoramic radiograph of family 1. (A) Pedigree of family 1. The black symbol indicates the affected individual, and the proband is indicated by a black arrow. Plus signs above the symbols indicate participating individuals. (B–F) Clinical photos of the proband at age 12 years. The maxillary right central incisor is discolored gray and ankylosed due to traumatic avulsion. Almost all teeth surfaces have irregular pits with external staining. (G) Panoramic radiograph of the proband at age 12 years. The enamel thickness seems within the normal range in general. There are no other abnormalities in the dentin or root forms.

Figure 2

Sequencing chromatograms. Normal nucleotides (with a black bar above the sequence) in the upper chromatogram of the normal individual, IV:2, are deleted, and the novel nucleotides (with a red bar above the sequence) are inserted into the lower chromatogram of the proband, IV:4. The deletion and insertion mutations are described as c.2680_2699delinsACTATAGTT (NM_182758.4) and p.(Ser894Thrfs*15).

Figure 3

Pedigree, clinical photo, and panoramic radiograph of family 2. (A) Pedigree of family 2. The black symbol indicates the affected individual, and the proband is indicated by a black arrow. A plus sign above the symbol indicates participating individuals. (B–F) Clinical photo of the proband at age 11 years. His mild hypoplastic enamel has irregular hypoplastic pits with staining. (G) A panoramic radiograph of the proband at age 7 years shows an ectopic eruption of the bilateral maxillary first molars. The enamel looks hypoplastic, especially in the first molars.

Figure 4

Sequencing chromatograms. Heterozygous deletion of GAGCAGATCCGTG (with a red bar underneath the sequence) in the proband is shown on the left (forward) and right (reverse) sequencing chromatograms.

Figure 5

Haplotypes of previously reported family and the family 2 in this study. Disease allele (red color) seems to be identical by descent. Paternal alleles are shown on the left and maternal alleles (green) are shown on the right. Locations of the variants on the list are based on mRNA sequence NM_000228.3.