Premature Stop Codon inMMP20Causing Amelogenesis Imperfecta

Abstract

Proteolytic enzymes are necessary for the hardening of dental enamel during development, and mutations in the kallikrein 4 (KLK4) and enamelysin (MMP20) genes cause autosomal recessive amelogenesis imperfecta (ARAI). So far, only one KLK4 and two MMP20 mutations have been reported. We have identified an ARAI-causing point mutation (c.l02G>A, g.l02G>A, and p.W34X) in exon 1 of MMP20 in a proband with autosomal recessive hypoplastic-hypomaturation amelogenesis imperfecta. The G to A transition changes the tryptophan (W) codon (TGG) at amino acid position 34 into a translation termination (X) codon (TGA). No disease-causing sequence variations were detected in KLK4. The affected enamel is thin, with mild spacing in the anterior dentition. The enamel layer is hypomineralized, does not contrast with dentin on radiographs, and tends to chip away from the underlying dentin. An intrinsic yellowish pigmentation is evident even during eruption. The phenotype supports current ideas concerning the function of enamelysin.

Pseudogenization of the tooth gene enamelysin (MMP20) in the common ancestor of extant baleen whales

“…One of these mutations encodes a stop signal in the propeptide-coding region of exon 1 [30]. Enamel in the afflicted individual is thin, hypomineralized and chips Tooth gene evolution in baleen whales R. W. Meredith et al 995 away from the underlying dentin [30]. Disease-causing SINE insertions in exons are sometimes associated with multiple transcripts, including mRNAs in which the SINE-afflicted exon has been spliced out [46].…”

“…Three mutations in the human MMP20 gene that cause amelogenesis imperfecta have been characterized, and in every case the inheritance pattern is autosomal recessive. One of these mutations encodes a stop signal in the propeptide-coding region of exon 1 [30]. Enamel in the afflicted individual is thin, hypomineralized and chips Tooth gene evolution in baleen whales R. W. Meredith et al 995 away from the underlying dentin [30].…”

“…MMP20-deficient mice have an amelogenesis imperfecta phenotype that is characterized by thin, hypomineralized enamel that easily chips away from the underlying dentin [31,32]. There are also mutations in the human MMP20 gene that cause non-syndromic amelogenesis imperfecta [30]. Other evidence suggests a role for MMP20, along with matrix metalloproteinase 2 (MMP2), in cleaving dentin sialophosphoprotein (DSPP), which consists of three parts: dentin sialoprotein (DSP), dentin glycoprotein (DGP) and dentin phosphoprotein (DPP) [33].…”

“…MMP20 diverged from other matrix metalloproteinase loci prior to the common ancestry of tetrapods [24], and plays a key role in processing structural proteins (amelogenin, ameloblastin, enamelin) that are secreted into the extracellular matrix by ameloblasts during the secretory stage of enamel formation [23,25 -28]. MMP20 may also be necessary to activate kallikreinrelated peptidase 4 (KLK4; [29,30]), which cleaves and degrades remnants of enamel matrix proteins during the maturation stage of amelogenesis. MMP20-deficient mice have an amelogenesis imperfecta phenotype that is characterized by thin, hypomineralized enamel that easily chips away from the underlying dentin [31,32].…”

Functions of KLK4 and MMP-20 in dental enamel formation

“…Eventually it was demonstrated that two proteases are involved: matrix metalloproteinase 20 (Bartlett et al, 1996) and kallikrein 4 . These enzymes undoubtedly play critical roles in dental enamel formation, as mutations in MMP20 and KLK4 cause autosomal recessive amelogenesis imperfecta (Hart et al, 2004;Kim et al, 2005;Ozdemir et al, 2005;Papagerakis et al, 2008). The functions of MMP-20 and KLK4 are best explained in the context of how enamel forms.…”