Novel ENAM mutation responsible for autosomal recessive amelogenesis imperfecta and localised enamel defects

Abstract

The genetic basis of non-syndromic autosomal recessive forms of amelogenesis imperfecta (AI) is unknown. To evaluate five candidate genes for an aetiological role in AI. In this study 20 consanguineous families with AI were identified in whom probands suggested autosomal recessive transmission. Family members were genotyped for genetic markers spanning five candidate genes: AMBN and ENAM (4q13.3), TUFT1 (1q21), MMP20 (11q22.3-q23), and KLK4 (19q13). Genotype data were evaluated to identify homozygosity in affected individuals. Mutational analysis was by genomic sequencing. Homozygosity linkage studies were consistent for localisation of an AI locus in three families to the chromosome 4q region containing the ENAM gene. ENAM sequence analysis in families identified a 2 bp insertion mutation that introduced a premature stop codon in exon 10. All three probands were homozygous for the same g.13185_13186insAG mutation. These probands presented with a generalised hypoplastic AI phenotype and a class II openbite malocclusion. All heterozygous carriers of the g.13185_13186insAG mutation had localised hypoplastic enamel pitting defects, but none had AI or openbite. The phenotype associated with the g.13185_13186insAG ENAM mutation is dose dependent such that ARAI with openbite malocclusion segregates as a recessive trait, and enamel pitting as a dominant trait.T he amelogenesis imperfectas (AI) are a clinically and aetiologically heterogeneous group of heritable disorders characterised by qualitative or quantitative anomalies of enamel development. While syndromic and non-syndromic forms of AI are reported, non-syndromic forms are the most prevalent.1 2 Although multiple classifications systems have been proposed for this condition, our current understanding of its aetiology does not allow the development of a robust nosology to account for the phenotypic variability observed. [3][4][5]

Pangolin genomes and the evolution of mammalian scales and immunity

“…Most notable of these was ENAM, the largest protein of the enamel matrix and essential for normal tooth development (Meredith et al 2009). ENAM mutations can lead to enamel defects (Hart et al 2003). We identified several frameshift indels and premature stop codons in the ENAM genes of both the Malayan and Chinese pangolins (confirmed by Sanger sequencing; sample size = 8) ( Fig.…”

Human Kallikrein 4: Quantitative Study in Tissues and Evidence for Its Secretion into Biological Fluids

“…Drawing conclusions on possible functional similarities between murine or porcine EMSP1 proteins and human hK4 is hampered by the fact that the former have glycosylation patterns, molecular forms, and propeptides distinct from human hK4 (26 ). Recent findings, however, have excluded KLK4 as a candidate gene in amelogenesis imperfecta (27,28 ) but suggested possible involvement of KLK4 mutations as a cause of the recessive form of hypomaturation amelogenesis imperfecta (29 ).…”

Proteomics and Genetics of Dental Enamel

“…To date, seven different disease-causing mutations have been identifi ed in ENAM: p.K53X [Mardh et al, 2002], p.M71-Q157 [Kim et al, 2005b], p.A158-Q178del [Rajpar et al, 2001], p.N197fsX277 [Kida et al, 2002;Hart et al, 2003a;Kim et al, 2005b], p.V340-M341insSQYQYCV [Ozdemir et al, 2005a], and p.P422fsX448 [Hart et al, 2003b;Ozdemir et al, 2005a]. The dental phenotype can be as minor as circumscribed enamel pits on the buccal surfaces of the anterior teeth and occlusal surfaces of posterior teeth, but more typically, the enamel is thinner than normal, with horizontal banding especially near to the cemento-enamel junction.…”