LAMB3 Mutations Causing Autosomal-dominant Amelogenesis Imperfecta

Abstract

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 COL17A1, LAMA3, LAMB3, or LAMC2. In rare cases, heterozygous carriers in JEB kindreds display enamel malformations in the absence of skin fragility (isolated AI). We recruited two kindreds with autosomaldominant 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 LAMB3 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_3453del GACTGGAG) shifted the reading frame (p.Gly 1149Glufs*8). In Family 2, a single nucleotide substitution (c.C3431A) generated an inframe translation termination codon (p.Ser1144*). 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.

Carriers with functional null mutations in LAMA3 have localized enamel abnormalities due to haploinsufficiency

“…LAMA3 null mutation carriers show minor enamel changes, whereas carriers with LAMB3 mutations have deeper pits and visible grooves requiring medical attention. [10][11][12] Extensive restorative dental care and multiple extractions such as described by Poulter et al for LAMB3 (NM_000228.2) carriers were not present in our LAMA3 carriers. A difference in the reported cases is that in LAMB3 carriers, dental abnormalities are associated with mutations that are predicted to escape nonsense mediated RNA decay (NMD, Table 1).…”

“…2,5,[10][11][12][13][14] In the examined heterozygous null carriers in both our families, dental pathology was localized focally, clinically asymptomatic and therefore not brought to attention until we examined JEB in their offspring. Since the first report of enamel abnormalities in LAMA3 null mutation carriers by Yuen et al, 5 we began to screen carriers of LAMA3 mutations for dental pitting.…”

“…In teeth, LM-332 is known to be a principal anchoring protein actively involved in the secretory stage of ameloblasts, an early stage of differentiation. 10 Amelogenesis is a tightly regulated process in which ameloblasts express LM-332. 3 Replacement of the lamina basale during amelogenesis is impaired if LM-332 is altered.…”

Mouse Genetic Background Influences the Dental Phenotype

“…Additional gene mutations in FAMC83H and WDR72, which encode ameloblast intracellular proteins, are associated with AI (Lee et al, 2008; El-Sayed et al, 2009). Recently C4orf26, which encodes a putative extracellular acidic phosphoprotein, and LAMB3 which encodes a protein previously linked to the syndrome junctional epidermolysis bullosa, have been shown when mutated to be causative for AI (Parry et al, 2012; Kim et al, 2013). In addition, enamel defects can be part of syndromes including junctional epidermolysis bullosa and TDO (tricho-dento-osseous) syndrome (Wright et al, 1993, 1997).…”

Triagem de mutações e polimorfismos de genes candidatos à malformação dentária em pacientes com fissura labiopalatinas

“…De acordo com a literatura, os principais genes envolvidos na formação do esmalte dentário são: amelogenina ligado ao X (AMELX), enamelina (ENAM), ameloblastina (AMBN), metaloprotease da matriz-20 (MMP-20) e calicreína-4 (KLK-4) (STEPHANOPOULOS; GAREFALAKI; LYROUDIA, 2005;WRIGHT et al, 2009;WRIGHT et al, 2011). Recentes análises genéticas têm identificado mutações em FAM83H (KIM et al, 2008), WDR72 (EL-SAYED et al, 2009;LEE et al, 2010), FAM20A (O'SULLIVAN et al, 2011CHO et al, 2012), C4orf26 (PARRY et al, 2012, SLC24A4 (PARRY et al, 2013), LAMB3 (KIM et al, 2013;POULTER et al, 2014b;WANG et al, 2015) e ITGB6 (POULTER et al, 2014a;WANG et al, 2014 Apesar dos defeitos na formação do esmalte dentário não compreenderem um problema de saúde pública, podem causar alterações estéticas graves, além de comprometerem as estruturas do esmalte. As formas severas podem levar à perda precoce do esmalte, causando desgaste acentuado com prejuízo da função do órgão dentário.…”