Limited phenotypic variation of hypocalcified amelogenesis imperfecta in a Danish five-generation family with a novel FAM83H nonsense mutation

Abstract

BACKGROUND. Autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI) is a disease with severe dental manifestations. OBJECTIVES. The aims were by means of a genome-wide linkage scan to search for the gene underlying the ADHCAI phenotype in a Danish five-generation family and to study the phenotypic variation of the enamel in affected family members. RESULTS. Significant linkage was found to a locus at chromosome 8q24.3 comprising the gene FAM83H identified to be responsible for ADHCAI in other families. Subsequent sequencing of FAM83H in affected family members revealed a novel nonsense mutation, p.Y302X. Limited phenotypic variation was found among affected family members with loss of translucency and discoloration of the enamel. Extensive posteruptive loss of enamel was found in all teeth of affected subjects. The tip of the cusps on the premolars and molars and a zone along the gingival margin seemed resistant to posteruptive loss of enamel. We have screened FAM83H in another five unrelated Danish patients with a phenotype of ADHCAI similar to that in the five-generation family, and identified a de novo FAM83H nonsense mutation, p.Q452X in one of these patients. CONCLUSION. We have identified a FAM83H mutation in two of six unrelated families with ADHCAI and found limited phenotypic variation of the enamel in these patients.

Amelogenin gene influence on enamel defects of cleft lip and palate patients

“…: amelogenin (AMELX), enamelin (ENAM), kallikrein-4 (KLK-4), matrix metalloprotease-20 (MMP-20), ameloblastin 3 and more recently DLX3, 4 FAM83H, 5,6,7 WDR72 5 and SLC4A4. 8 AMELX encodes a member of the amelogenin family of extracellular matrix protein and has an important role in biomineralization during tooth enamel development.…”

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

“…Alguns genes que codificam proteínas específicas do esmalte têm sido identificados com genes candidatos para malformações dentárias. Análises mutacionais, com estudo de famílias, têm suportado esta hipótese (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 Sabe-se que as proteínas geradas a partir das mutações genéticas detectadas têm a estrutura alterada, desta forma, estudos futuros são necessários, para elucidar se essas proteínas têm também a função prejudicada no organismo humano. A adição de informações genéticas sobre malformações dentárias poderá proporcionar novas oportunidades para mapear os genes candidatos para fissuras labiopalatinas.…”

“…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.…”