Dental enamel malformations, or amelogenesis imperfecta (AI), can be isolated or syndromic. To improve the prospects of making a successful diagnosis by genetic testing, it is important that the full range of genes and mutations that cause AI be determined. Defects in WDR72 (WD repeat-containing protein 72; OMIM *613214) cause AI, type IIA3 (OMIM #613211), which follows an autosomal recessive pattern of inheritance. The defective enamel is normal in thickness, severely hypomineralized, orange-brown stained, and susceptible to attrition. We identified 6 families with biallelic WDR72 mutations by whole exome sequence analyses that perfectly segregated with the enamel phenotype. The novel mutations included 3 stop-gains [NM_182758.2: c.377G>A/p.(Trp126*), c.1801C>T/p.(Arg601*), c.2350A>T/p.(Arg784*)], a missense mutation [c.1265G>T/p.(Gly422Val)], and a 62,138–base pair deletion (NG_017034.2: g.35441_97578del62138) that removed WDR72 coding exons 3 through 13. A previously reported WDR72 frameshift was also observed [c.1467_1468delAT/p.(Val491Aspfs*8)]. Three of the affected patients showed decreased serum pH, consistent with a diagnosis of renal tubular acidosis. Percentiles of stature and body weight varied among 8 affected individuals but did not show a consistent trend. These studies support that WDR72 mutations cause a syndromic form of AI and improve our ability to diagnose AI caused by WDR72 defects.
AdzhubeiIJordanDMSunyaevSR. 2013. Predicting functional effect of human missense mutations using polyphen-2. Curr Protoc Hum Genet. Chap 7, unit7.20.
2.
BardetCCoursonFWuYKhaddamMSalmonBRibesSThumfartJYamagutiPMRochefortGYFigueresML, et al. 2016. Claudin-16 deficiency impairs tight junction function in ameloblasts, leading to abnormal enamel formation. J Bone Miner Res. 31(3):498–513.
3.
Burgueno TorresLMourelle MartinezMRde Nova GarciaJM. 2015. A study on the chronology and sequence of eruption of primary teeth in Spanish children. Eur J Paediatr Dent. 16(4):301–304.
4.
CaliskanEAcikgozGYeniayYOzmenIGamsizkanMAkarA.2015. A case of Marshall’s syndrome and review of the literature. Int J Dermatol. 54(6):e217–e221.
5.
El-SayedWParryDAShoreRCAhmedMJafriHRashidYAl-BahlaniSAl HarasiSKirkhamJInglehearnCF, et al. 2009. Mutations in the beta propeller WDR72 cause autosomal-recessive hypomaturation amelogenesis imperfecta. Am J Hum Genet. 85(5):699–705.
6.
El-SayedWShoreRCParryDAInglehearnCFMighellAJ. 2011. Hypomaturation amelogenesis imperfecta due to WDR72 mutations: a novel mutation and ultrastructural analyses of deciduous teeth. Cells Tissues Organs. 194(1):60–66.
7.
EXaC project pins down rare gene variants. 2016. Nature. 536(7616):249.
8.
FranceschiniNHaackKAlmasyLLastonSLeeETBestLGFabsitzRRMacCluerJWHowardBVUmansJG, et al. 2014. Generalization of associations of kidney-related genetic loci to American Indians. Clin J Am Soc Nephrol. 9(1):150–158.
9.
HentschelJTatunDParkhomchukDKurthISchimmelBHeinrich-WeltzienRBertzbachSPetersHBeetzC.2016. Identification of the first multi-exonic WDR72 deletion in isolated amelogenesis imperfecta, and generation of a WDR72-specific copy number screening tool. Gene. 590(1):1–4.
10.
HiguchiYHasegawaKYamashitaMTanakaHTsukaharaH.2017. A novel mutation in the COL2A1 gene in a patient with stickler syndrome type 1: a case report and review of the literature. J Med Case Rep. 11(1):237.
11.
HintzscheJKimJYadavVAmatoCRobinsonSESeelenfreundEShellmanYWisellJApplegateAMcCarterM, et al. 2016. Impact: a whole-exome sequencing analysis pipeline for integrating molecular profiles with actionable therapeutics in clinical samples. J Am Med Inform Assoc. 23(4):721–730.
12.
IgarashiTInatomiJSekineTChaSHKanaiYKunimiMTsukamotoKSatohHShimadzuMTozawaF, et al. 1999. Mutations in SLC4A4 cause permanent isolated proximal renal tubular acidosis with ocular abnormalities. Nat Genet. 23(3):264–266.
13.
JalaliRGuoJZandieh-DoulabiBBervoetsTJPaineMLBoronWFParkerMDBijveldsMJMedinaJFDenBestenPK, et al. 2014. NBCe1 (SLC4A4) a potential pH regulator in enamel organ cells during enamel development in the mouse. Cell Tissue Res. 358(2):433–442.
14.
JaureguiberryGDe la Dure-MollaMParryDQuentricMHimmerkusNKoikeTPoulterJKlootwijkERobinetteSLHowieAJ, et al. 2012. Nephrocalcinosis (enamel renal syndrome) caused by autosomal recessive FAM20A mutations. Nephron Physiol. 122(1–2):1–6.
15.
KatsuraKAHorstJAChandraDLeTQNakanoYZhangYHorstOVZhuLLeMHDenBestenPK. 2014. WDR72 models of structure and function: a stage-specific regulator of enamel mineralization. Matrix Biol. 38:48–58.
16.
KottgenAPattaroCBogerCAFuchsbergerCOldenMGlazerNLParsaAGaoXYangQSmithAV, et al. 2010. New loci associated with kidney function and chronic kidney disease. Nat Genet. 42(5):376–384.
17.
KuechlerAHentschelJKurthIStephanBProttECSchweigerBSchusterAWieczorekDLudeckeHJ. 2012. A novel homozygous WDR72 mutation in two siblings with amelogenesis imperfecta and mild short stature. Mol Syndromol. 3(5):223–229.
18.
LacruzRSSmithCEKurtzIHubbardMJPaineML. 2013. New paradigms on the transport functions of maturation-stage ameloblasts. J Dent Res. 92(2):122–129.
19.
LeBlancMKulleBSundetKAgartzIMelleIDjurovicSFrigessiAAndreassenOA. 2012. Genome-wide study identifies PTPRO and WDR72 and FOXQ1-SUMO1P1 interaction associated with neurocognitive function. J Psychiatr Res. 46(2):271–278.
20.
LeeSKSeymenFLeeKEKangHYYildirimMTunaEBGencayKHwangYHNamKHDe La GarzaRJ, et al. 2010. Novel WDR72 mutation and cytoplasmic localization. J Dent Res. 89(12):1378–1382.
21.
MisgarRAHassanZWaniAIBashirMI. 2017. Amelogenesis imperfecta with distal renal tubular acidosis: a novel syndrome? Indian J Nephrol. 27(3):225–227.
22.
PrasadMKGeoffroyVVicaireSJostBDumasMLe GrasSSwitalaMGasseBLaugel-HaushalterVPaschakiM, et 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.
23.
RaimondeauEBuftonJCSchaffitzelC.2018. New insights into the interplay between the translation machinery and nonsense-mediated mRNA decay factors. Biochem Soc Trans. 46(3):503–512.
24.
RaviPEkambaranathTSArasiSEFernandoE.2013. Distal renal tubular acidosis and amelogenesis imperfecta: a rare association. Indian J Nephrol. 23(6):452–455.
25.
RungrojNNettuwakulCSawasdeeNSangnualSDeejaiNMisgarRAPasenaAKhositsethSKirdponSSritippayawanS, et al. 2018. Distal renal tubular acidosis caused by tryptophan-aspartate repeat domain 72 (WDR72) mutations. Clin Genet. 94(5):409–418.
26.
SimNLKumarPHuJHenikoffSSchneiderGNgPC. 2012. SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res. 40(Web Server issue):W452–W457.
SimmerJPPapagerakisPSmithCEFisherDCRountreyANZhengLHuJC. 2010. Regulation of dental enamel shape and hardness. J Dent Res. 89(10):1024–1038.
29.
SimmerJPRichardsonASHuYYSmithCEHuJC-C. 2012. A post-classical theory of enamel biomineralization . . . and why we need one. Int J Oral Sci. 4(3):129–134.
30.
SimmerJPRichardsonASWangSKReidBMBaiYHuYHuJC. 2014. Ameloblast transcriptome changes from secretory to maturation stages. Connect Tissue Res. 55 Suppl1:29–32.
31.
SmithCE. 1998. Cellular and chemical events during enamel maturation. Crit Rev Oral Biol Med. 9(2):128–161.
32.
SmithCELPoulterJAAntanaviciuteAKirkhamJBrookesSJInglehearnCFMighellAJ. 2017. Amelogenesis imperfecta: genes, proteins, and pathways. Front Physiol. 8:435.
33.
SpringerMSStarrettJMorinPALanzettiAHayashiCGatesyJ.2016. Inactivation of C4orf26 in toothless placental mammals. Mol Phylogenet Evol. 95:34–45.
WangSKArefPHuYMilkovichRNSimmerJPEl-KhateebMDaggagHBaqainZHHuJC. 2013. FAM20A mutations can cause enamel-renal syndrome (ERS). PLoS Genet. 9(2):e1003302.
36.
WangSKHuYYangJSmithCENunezSMRichardsonASPalSSamannACHuJCSimmerJP. 2015. Critical roles for WDR72 in calcium transport and matrix protein removal during enamel maturation. Mol Genet Genomic Med. 3(4):302–319.
37.
WinsnesAMonnEStokkeOFeylingT.1979. Congenital persistent proximal type renal tubular acidosis in two brothers. Acta Paediatr Scand. 68(6):861–868.
38.
WrightJTCarrionIAMorrisC.2015. The molecular basis of hereditary enamel defects in humans. J Dent Res. 94(1):52–61.
XuCMinJ.2011. Structure and function of WD40 domain proteins. Protein Cell. 2(3):202–214.
41.
YamagutiPMNevesFAHottonDBardetCde La Dure-MollaMCastroLCScherMDBarbosaMEDitschCFricainJC, et al. 2017. Amelogenesis imperfecta in familial hypomagnesaemia and hypercalciuria with nephrocalcinosis caused by CLDN19 gene mutations. J Med Genet. 54(1):26–37.
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