LAMB3 mutations causing autosomal-dominant amelogenesis imperfecta.

[junctional epidermolysis bullosa]

Amelogenesis imperfecta (AI ) can be either isolated or part of a larger syndrome . Junctional epidermolysis bullosa (JEB ) is a collection of autosomal-recessive disorders featuring AI associated with skin fragility and other symptoms . JEB is a recessive syndrome usually caused by mutations in both alleles of COL 17 A 1 , LAMA 3 , LAMB 3 , or LAMC 2 . In rare cases , heterozygous carriers in JEB kindreds display enamel malformations in the absence of skin fragility (isolated AI ). We recruited two kindreds with autosomal-dominant amelogenesis imperfecta (ADAI ) characterized by generalized severe enamel hypoplasia with deep linear grooves and pits . Whole-exome sequencing of both probands identified novel heterozygous mutations in the last exon of LAMB 3 that likely truncated the protein . The mutations perfectly segregated with the enamel defects in both families . In Family 1 , an 8 -bp deletion (c .3446 _3453 del GACTGGAG ) shifted the reading frame (p .Gly 1149 Glufs *8 ). In Family 2 , a single nucleotide substitution (c .C 3 431 A ) generated an in -frame translation termination codon (p .Ser 1144 *). We conclude that enamel formation is particularly sensitive to defects in hemidesmosome /basement-membrane complexes and that syndromic and non-syndromic forms of AI can be etiologically related .