Amelogenesis imperfecta (AI) is a group of genetic disorders of defective dental enamel. Mutation of AMELX encoding amelogenin on the X chromosome is a major cause of AI. Here we report a Chinese family with hypoplastic and hypomineralized AI. Whole exome analysis revealed a novel mutation c.185delC in exon 5 of AMELX causing the frame shift p.Pro62ArgfsTer47 (or p.Pro62Argfs*47). By sequencing of polymerase chain reaction products and T-vector clones, the mutation was confirmed as homozygous in the proband, hemizygous in her father, and heterozygous in her mother. The proband and her father had small and yellowish teeth with thin and rough enamel that was radiographically indistinguishable from the underlying dentin. Scanning electronic microscopy of 1 maternal tooth showed cracks and exposed loosely packed enamel prisms in affected areas. Consistent with a 25:75 skewing of X inactivation in the peripheral blood DNA as measured by androgen receptor allele methylation, the surface of the mother’s tooth had alternating vertical ridges of transparent normal and white chalky enamel in a 34:66 ratio. In summary, this study provides one of the few phenotypic comparisons of hemizygous and homozygous AMELX mutations and suggests that the skewing of X inactivation in AI contributes to the phenotypic variations in heterozygous carriers of X-linked AI.
AgulnikAIMitchellMJMatteiMGBorsaniGAvnerPALernerJLBishopCE. 1994. A novel X gene with a widely transcribed Y-linked homologue escapes X-inactivation in mouse and human. Hum Mol Genet. 3(6):879–884.
2.
AldredMJCrawfordPJRobertsEGillespieCMThomasNSFentonISandkuijlLAHarperPS. 1992. Genetic heterogeneity in X-linked amelogenesis imperfecta. Genomics. 14(3):567–573.
3.
AldredMJCrawfordPJRobertsEThomasNS. 1992. Identification of a nonsense mutation in the amelogenin gene (AMLEX) in a family with X-linked amelogenesis imperfecta (AIH1). Hum Genet. 90(4):413–416.
4.
AllenRCZoghbiHYMoseleyABRosenblattHMBelmontJW. 1992. Methylation of Hpall and Hhai sites near the polymorphic cag repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet. 51(6):1229–1239.
5.
BansalAKShettyDCBindalRPathakA.2012. Amelogenin: a novel protein with diverse applications in genetic and molecular profiling. J Oral Maxillofac Pathol. 16(3):395–399.
6.
BarronMJBrookesSJKirkhamJShoreRCHuntCMironovAKingswellNJMaycockJShuttleworthCADixonMJ. 2010. A mutation in the mouse amelx tri-tyrosyl domain results in impaired secretion of amelogenin and phenocopies human X-linked amelogenesis imperfecta. Hum Mol Genet. 19(7):1230–1247.
7.
BerkmanMDSingerA. 1971. Demonstration of the lyon hypothesis in X-linked dominant hypoplastic amelogenesis imperfecta. Birth Defects Orig Artic Ser. 7(7):204–209.
8.
ChoESKimKJLeeKELeeEJYunCYLeeMJShinTJHyunHKKimYJLeeSH, et al. 2014. Alteration of conserved alternative splicing in AMELX causes enamel defects. J Dent Res. 93(10):980–987.
GibsonCWYuanZAHallBLongeneckerGChenEThyagarajanTSreenathTWrightJTDeckerSPiddingtonR, et al. 2001. Amelogenin-deficient mice display an amelogenesis imperfecta phenotype. J Biol Chem. 276(34):31871–31875.
11.
GreeneSRYuanZAWrightJTAmjadHAbramsWRBuchananJATrachtenbergDIGibsonCW. 2002. A new frameshift mutation encoding a truncated amelogenin leads to X-linked amelogenesis imperfecta. Arch Oral Biol. 47(3):211–217.
12.
HartPSAldredMJCrawfordPJWrightNJHartTCWrightJT. 2002. Amelogenesis imperfecta phenotype-genotype correlations with two amelogenin gene mutations. Arch Oral Biol. 47(4):261–265.
13.
HartPSHartTCSimmerJPWrightJT. 2002. A nomenclature for X-linked amelogenesis imperfecta. Arch Oral Biol. 47(4):255–260.
14.
HartSHartTGibsonCWrightJT. 2000. Mutational analysis of X-linked amelogenesis imperfecta in multiple families. Arch Oral Biol. 45(1):79–86.
15.
HobsonGMGibsonCWAragonMYuanZADavis-WilliamsABanserLKirkhamJBrookAH. 2009. A large X-chromosomal deletion is associated with microphthalmia with linear skin defects (MLS) and amelogenesis imperfecta (XAI). Am J Med Genet A. 149(8):1698–1705.
16.
HuJCChanHCSimmerSGSeymenFRichardsonASHuYMilkovichRNEstrellaNMYildirimMBayramM, et al. 2012. Amelogenesis imperfecta in two families with defined AMELX deletions in ARHGAP6. PLoS One. 7(12):e52052.
17.
KidaMSakiyamaYMatsudaATakabayashiSOchiHSekiguchiHMinamitakeSArigaT. 2007. A novel missense mutation (p.P52r) in amelogenin gene causing X-linked amelogenesis imperfecta. J Dent Res. 86(1):69–72.
KimJWZhangHSeymenFKoruyucuMHuYKangJKimYJIkedaAKasimogluYBayramM, et al. 2018. Mutations in RELT cause autosomal recessive amelogenesis imperfecta. Clin Genet. 95(3):375–383.
KindelanSABrookAHGangemiLLenchNWongFSFearneJJacksonZFosterGStringerBM. 2000. Detection of a novel mutation in X-linked amelogenesis imperfecta. J Dent Res. 79(12):1978–1982.
22.
LagerstromMDahlNNakahoriYNakagomeYBackmanBLandegrenUPetterssonU. 1991. A deletion in the amelogenin gene (AMG) causes X-linked amelogenesis imperfecta (AIH1). Genomics. 10(4):971–975.
23.
Lagerstrom-FermerMNilssonMBackmanBSalidoEShapiroLPetterssonULandegrenU. 1995. Amelogenin signal peptide mutation: correlation between mutations in the amelogenin gene (AMGX) and manifestations of X-linked amelogenesis imperfecta. Genomics. 26(1):159–162.
24.
LauECMohandasTKShapiroLJSlavkinHCSneadML. 1989. Human and mouse amelogenin gene loci are on the sex chromosomes. Genomics. 4(2):162–168.
25.
LeeKELeeSKJungSESongSJChoSHLeeZHKimJW. 2011. A novel mutation in the AMELX gene and multiple crown resorptions. Eur J Oral Sci. 119Suppl 1:324–328.
26.
LenchNJWinterGB. 1995. Characterisation of molecular defects in X-linked amelogenesis imperfecta (AIH1). Hum Mutat. 5(3):251–259.
27.
MigeonBR. 2017. Choosing the active X: the human version of X inactivation. Trends Genet. 33(12):899–909.
28.
MinksJRobinsonWPBrownCJ. 2008. A skewed view of X chromosome inactivation. J Clin Invest. 118(1):20–23.
29.
OliveiraFVDionisioTJNevesLTMachadoMASantosCFOliveiraTM. 2014. Amelogenin gene influence on enamel defects of cleft lip and palate patients. Braz Oral Res. 28(1).
30.
PaineMLZhuDHLuoWBringasPJr.GoldbergMWhiteSNLeiYPSarikayaMFongHKSneadML. 2000. Enamel biomineralization defects result from alterations to amelogenin self-assembly. J Struct Biol. 132(3):191–200.
31.
SalidoECYenPHKoprivnikarKYuLCShapiroLJ. 1992. The human enamel protein gene amelogenin is expressed from both the X and the Y chromosomes. Am J Hum Genet. 50(2):303–316.
32.
SekiguchiHAlaluusuaSMinaguchiKYakushuiM. 2001. A new mutation in the amelogenin gene causes X-linked amelogenesis imperfecta. J Dent Res. 80Suppl 2: 617. (Abstract 0722)
33.
SekiguchiHKiyoshiM.YakushijiM. 2001. DNA diagnosis of X-linked amelogensis imperfecta using PCR detection method of the human amelogenin gene. Dent Jpn. 37:109–112.
34.
SmithCELPoulterJAAntanaviciuteAKirkhamJBrookesSJInglehearnCFMighellAJ. 2017. Amelogenesis imperfecta; genes, proteins, and pathways. Front Physiol. 8:435.
35.
SneadMLLuoWLauECSlavkinHC. 1988. Spatial- and temporal-restricted pattern for amelogenin gene expression during mouse molar tooth organogenesis. Development. 104(1):77–85.
36.
van DijkJPHeuverLStevens-LindersEJansenJHMensinkEJRaymakersRAde WitteT. 2002. Acquired skewing of lyonization remains stable for a prolonged period in healthy blood donors. Leukemia. 16(3):362–367.
37.
WitkopCJJr.1967. Partial expression of sex-linked recessive amelogenesis imperfecta in females compatible with the Lyon hypothesis. Oral Surg Oral Med Oral Pathol. 23(2):174–182.
38.
WrightJTHallKIYamaucheM. 1997. The enamel proteins in human amelogenesis imperfecta. Arch Oral Biol. 42(2):149–159.
39.
WrightJTHartPSAldredMJSeowKCrawfordPJHongSPGibsonCWHartTC. 2003. Relationship of phenotype and genotype in X-linked amelogenesis imperfecta. Connect Tissue Res. 44Suppl 1:72–78.
40.
ZhangYKeYZhengXLiuQDuanX. 2017. Correlation between genotype and phenotype in three families with Peutz-Jeghers syndrome. Exp Ther Med. 13(2):507–514.
41.
ZvejnieksPATellschowSRGudlaugssonEGMarkhamNShroyerKR. 1998. Amelogenin dosage compensation in carcinoma of colon, lung, liver and kidney, is not a marker of clonality in males. Mol Cell Probes. 12(4):185–190.
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