Tooth enamel, the hardest tissue in the human body, is formed after a complex series of interactions between dental epithelial tissue and the underlying ectomesenchyme. Nonsyndromic amelogenesis imperfecta (AI) is a rare genetic disorder affecting tooth enamel without other nonoral symptoms. In this study, we identified 2 novel ENAM mutations in 2 families with hypoplastic AI by whole exome sequencing. Family 1 had a heterozygous splicing donor site mutation in intron 4, NM_031889; c.123+2T>G. Affected individuals had hypoplastic enamel with or without the characteristic horizontal hypoplastic grooves in some teeth. Family 2 had a nonsense mutation in the last exon, c.1842C>G, p.(Tyr614*), that was predicted to truncate the protein by 500 amino acids. Participating individuals had at least 1 mutant allele, while the proband had a homozygous mutation. Most interestingly, the clinical phenotype of the individuals harboring the heterozygous mutation varied from a lack of penetrance to a mild hypoplastic enamel defect. We believe that these findings will broaden our understanding of the clinical phenotype of AI caused by ENAM mutations.
El-SayedWParryDAShoreRCAhmedMJafriHRashidYAl-BahlaniSAl HarasiSKirkhamJInglehearnCFet al. 2009. Mutations in the beta propeller WDR72 cause autosomal-recessive hypomaturation amelogenesis imperfecta. Am J Hum Genet. 85(5):699–705.
2.
HartPSHartTCMichalecMDRyuOHSimmonsDHongSWrightJT. 2004. Mutation in kallikrein 4 causes autosomal recessive hypomaturation amelogenesis imperfecta. J Med Genet. 41(7):545–549.
3.
HartPSMichalecMDSeowWKHartTCWrightJT. 2003. Identification of the enamelin (g.8344delG) mutation in a new kindred and presentation of a standardized ENAM nomenclature. Arch Oral Biol. 48(8):589–596.
4.
HartTCHartPSGorryMCMichalecMDRyuOHUygurCOzdemirDFiratliSArenGFiratliE.2003. Novel ENAM mutation responsible for autosomal recessive amelogenesis imperfecta and localised enamel defects. J Med Genet. 40(12):900–906.
5.
HintzscheJDRobinsonWATanAC. 2016. A survey of computational tools to analyze and interpret whole exome sequencing data. Int J Genomics. 2016:7983236.
KidaMArigaTShirakawaTOguchiHSakiyamaY.2002. Autosomal-dominant hypoplastic form of amelogenesis imperfecta caused by an enamelin gene mutation at the exon-intron boundary. J Dent Res. 81(11):738–742.
10.
KimJWLeeSKLeeZHParkJCLeeKELeeMHParkJTSeoBMHuJCSimmerJP. 2008. FAM83H mutations in families with autosomal-dominant hypocalcified amelogenesis imperfecta. Am J Hum Genet. 82(2):489–494.
11.
KimJWSeymenFLinBPKiziltanBGencayKSimmerJPHuJC. 2005. Enam mutations in autosomal-dominant amelogenesis imperfecta. J Dent Res. 84(3):278–282.
12.
KimJWSimmerJPHartTCHartPSRamaswamiMDBartlettJDHuJC. 2005. MMP-20 mutation in autosomal recessive pigmented hypomaturation amelogenesis imperfecta. J Med Genet. 42(3):271–275.
13.
KimYHurSWJeongBCOhSHHwangYCKimSHKohJT. 2018. The Fam50a positively regulates ameloblast differentiation via interacting with Runx2. J Cell Physiol. 233(2):1512–1522.
14.
LagerstromMDahlNNakahoriYNakagomeYBackmanBLandegrenUPetterssonU.1991. A deletion in the amelogenin gene (AMG) causes X-linked amelogenesis imperfecta (AIH1). Genomics. 10(4):971–975.
15.
LeeKEKoJLeCGShinTJHyunHKLeeSHKimJW. 2015. Novel LAMB3 mutations cause non-syndromic amelogenesis imperfecta with variable expressivity. Clin Genet. 87(1):90–92.
16.
McGrathJAGatalicaBLiKDunnillMGMcMillanJRChristianoAMEadyRAUittoJ.1996. Compound heterozygosity for a dominant glycine substitution and a recessive internal duplication mutation in the type XVII collagen gene results in junctional epidermolysis bullosa and abnormal dentition. Am J Pathol. 148(6):1787–1796.
17.
MillerJNPearceDA. 2014. Nonsense-mediated decay in genetic disease: friend or foe?Mutat Res Rev Mutat Res. 762:52–64.
18.
ParryDABrookesSJLoganCVPoulterJAEl-SayedWAl-BahlaniSAl HarasiSSayedJRaifEMShoreRCet al. 2012. Mutations in C4orf26, encoding a peptide with in vitro hydroxyapatite crystal nucleation and growth activity, cause amelogenesis imperfecta. Am J Hum Genet. 91(3):565–571.
19.
ParryDAPoulterJALoganCVBrookesSJJafriHFergusonCHAnwariBMRashidYZhaoHJohnsonCAet al. 2013. Identification of mutations in SLC24A4, encoding a potassium-dependent sodium/calcium exchanger, as a cause of amelogenesis imperfecta. Am J Hum Genet. 92(2):307–312.
20.
ParryDASmithCEEl-SayedWPoulterJAShoreRCLoganCVMogiCSatoKOkajimaFHaradaAet al. 2016. Mutations in the pH-sensing G-protein-coupled receptor GPR68 cause amelogenesis imperfecta. Am J Hum Genet. 99(4):984–990.
21.
PavlicAPetelinMBattelinoT.2007. Phenotype and enamel ultrastructure characteristics in patients with ENAM gene mutations g.13185-13186insAG and 8344deLG. Arch Oral Biol. 52(3):209–217.
22.
PoulterJABrookesSJShoreRCSmithCEAbi FarrajLKirkhamJInglehearnCFMighellAJ. 2014. A missense mutation in ITGB6 causes pitted hypomineralized amelogenesis imperfecta. Hum Mol Genet. 23(8):2189–2197.
23.
PoulterJAEl-SayedWShoreRCKirkhamJInglehearnCFMighellAJ. 2014. Whole-exome sequencing, without prior linkage, identifies a mutation in LAMB3 as a cause of dominant hypoplastic amelogenesis imperfecta. Eur J Hum Genet. 22(1):132–135.
24.
PoulterJAMurilloGBrookesSJSmithCEParryDASilvaSKirkhamJInglehearnCFMighellAJ. 2014. Deletion of ameloblastin exon 6 is associated with amelogenesis imperfecta. Hum Mol Genet. 23(20):5317–5324.
25.
PrasadMKGeoffroyVVicaireSJostBDumasMLe GrasSSwitalaMGasseBLaugel-HaushalterVPaschakiMet al. 2016. A targeted next-generation sequencing assay for the molecular diagnosis of genetic disorders with orodental involvement. J Med Genet. 53(2):98–110.
SimmerJPRichardsonASHuYYSmithCEChing-Chun HuJ. 2012. A post-classical theory of enamel biomineralization . . . and why we need one. Int J Oral Sci. 4(3):129–134.
32.
SmithCEMurilloGBrookesSJPoulterJASilvaSKirkhamJInglehearnCFMighellAJ. 2016. Deletion of amelotin exons 3-6 is associated with amelogenesis imperfecta. Hum Mol Genet. 25(16):3578–3587.
33.
TanabeTAobaTMorenoECFukaeMShimuzuM.1990. Properties of phosphorylated 32 kd nonamelogenin proteins isolated from porcine secretory enamel. Calcif Tissue Int. 46(3):205–215.
YuenWYPasmooijAMStellingsmaCJonkmanMF. 2012. Enamel defects in carriers of a novel lama3 mutation underlying epidermolysis bullosa. Acta Derm Venereol. 92(6):695–696.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
