Amelogenesis Imperfecta: Genotype-Phenotype Studies in 71 Families

Abstract

Amelogenesis imperfecta (AI) represents hereditary conditions affecting the quality and quantity of enamel. Six genes are known to cause AI (AMELX, ENAM, MMP20, KLK4, FAM83H, and WDR72). Our aim was to determine the distribution of different gene mutations in a large AI population and evaluate phenotype-genotype relationships. Affected and unaffected family members were evaluated clinically and radiographically by one examiner. Genotyping was completed using genomic DNA obtained from blood or saliva. A total of 494 individuals were enrolled, with 430 (224 affected, 202 unaffected, and 4 not definitive) belonging to 71 families with conditions consistent with the diagnosis of AI. Diverse clinical phenotypes were observed (i.e. hypoplastic, hypocalcified, and hypomaturation). Genotyping revealed mutations in all 6 candidate genes. A molecular diagnosis was made in 132 affected individuals (59%) and in 26 of the families (37%). Mutations involved 12 families with FAM83H (46%), 6 families with AMELX (23%), 3 families with ENAM (11%), 2 families with KLK4 and MMP20 (8% for each gene), and 1 family with a WDR72 mutation (4%). Phenotypic variants were associated with allelic FAM83H and AMELX mutations. Two seemingly unrelated families had the same KLK4 mutation. Families affected with AI where candidate gene mutations were not identified could have mutations not identifiable by traditional gene sequencing (e.g. exon deletion) or they could have promoter sequence mutations not evaluated in this study. However, the results suggest that there remain new AI causative genes to be identified.

Genetic polymorphisms in the human tissue kallikrein (KLK) locus and their implication in various malignant and non-malignant diseases

“…The initial study identified a truncating mutation, p.W153X, in one AI family that occurs at a highly conserved tryptophan residue and results in a KLK4 protein lacking the S207 residue of the catalytic triad (Hart et al , 2004 ). Two further AI studies carried out using DNA from blood and saliva samples have identified several more Caucasian families carrying this mutation (Wright et al , 2009(Wright et al , , 2011, cementing KLK4 as a high-risk gene for this condition.…”

Estudo genético da mutação do gene AMELX na malformação dentária de pacientes com e sem fissura labiopalatina

“…De acordo com a literatura, alguns genes estão envolvidos na formação do esmalte dentário: amelogenina (AMELX), enamelisina (ENAM), calicreína-4 (KLK-4), metaloprotease da matriz , ameloblastina (Wright et al 2009) e, mais recentemente, os genes DLX3 (Stephanopoulos et al 2005), FAM83H (Wright et al 2011, Haubek et al 2011, WDR72 (Wright et al 2011) e SLC4A4 (Urzúa et al 2011).…”

“…Outros genes candidatos a mutações nas regiões codificadoras são responsáveis por diversos fenótipos clínicos de alterações no esmalte dentário, (Kim et al 2008, Wright et al 2011, Haubek et al 2011, Urzúa et al 2011. A mutação no gene WDR72 (Hartz et al 2010) causa AI tipo hipomaturada, localizada no cromossomo 15q21.3…”

“…Na literatura consultada, a maioria dos estudos analisou famílias com alterações dentárias (Hart et al 2002, Kim et al 2005a, Kim et al 2005b, Kim et al 2008, Stephanopoulos et al 2005, Wright et al 2009, Hart et al 2009, Wright et al 2011, Haubek et al 2011) e não grupos de pacientes com diferentes fenótipos e genótipos, como neste estudo.…”

“…A saliva é o material de partida para extração de DNA, citado na literatura de mais fácil acesso e não necessita de intervenção invasiva para a coleta (Vieira et al 2008a, Vieira et al 2008b, Neves 2009, Wright et al 2011), e por esse motivo, foi utilizada a saliva como material de partida para o sequenciamento do DNA. Nos diversos centros de pesquisa, estão sendo utilizados protocolos distintos para o preparo das amostras com vistas ao sequenciamento direto, cada um aplicado a um tipo de plataforma de sequenciamento (Stephanopoulos et al 2005, Neves 2009, Wright et al 2011, Urzúa et al 2011.…”