Novel FAM83H mutations in Turkish families with autosomal dominant hypocalcified amelogenesis imperfecta.

摘要: To the Editor: Amelogenesis imperfecta (AI) are a heterogeneous group of disorders that perturb enamel development. Historically, 14 subtypes have been recognized based on clinical phenotype and mode inheritance (1). date, mutations in AMELX, ENAM, KLK4, MMP20 documented hypoplastic hypomaturation AI (2–6). However, genetic basis for most cases autosomal dominant Turkish population remained unknown. Recently, underlying hypocalcified form were reported (7, 8). In present study, we evaluated eight kindreds with (ADHCAI). Genetic linkage studies consistent to chromosome 8q24.3 seven families. Sequence analysis identified FAM83H nonsense all families. Eight probands from Dental School Clinics at Ege University, University Istanbul Yeditepe Istanbul, Turkey, accordance Institutional Review Board approval corresponding National Institutes Health. Available family members received an oral examination dental radiographs determine affection status. The presence was established by generalized yellow–brown discoloration teeth, appearing pathological loss enamel. Affected individuals diagnosed ADHCAI previously proposed criteria (1) (Fig. 1). Seven transmission AI. eighth family, only proband affected, but known genes had excluded sequence analysis. A total 50 clinically examined, including 26 affected individuals. DNA extraction peripheral venous blood performed as described (6). saliva according Oragene protocol (DNA Genotek Inc., Ottawa, Ontario, Canada). Fig. 1 Pedigrees, photographs, haplotype families segregating amelogenesis imperfecta. (a) Family 1 mutation, c.1192C>T (p.Q398X). (b) ... Primers conditions used amplify gene shown Table 1. large approximately 4.8 kb exon 5 split into overlapping amplicons. Polymerase chain reaction (PCR) products purified using Exo-Sap sequenced both directions minimize sequencing artifacts ABI Big Dye Terminator chemistry, version 3.1, 3730 (Applied Biosystems, Foster City, CA). Table 1 Primers FAM83H Six short tandem repeat polymorphism (STRP) markers (D8S1836, D8S15018mg, D8S373, D8S2334, D8S1925 D8S1926) spanning 2.35-Mb interval includes locus genotyped. Markers amplified genomic fluorescently labeled primers AmpliTaq Gold PCR Master Mix Biosystems) manufacturer’s protocol. electrophoresed 3130 analyzer size standard GeneScan 400HD Rox. Data analyzed GeneMapper ID software, v3.7. Haplotypes generated allele transmission, incorporating variants sequencing. Genotyping STRP loci surrounding 1–7 this eight. As unable published (7), redesigned required variety successfully region. Three 1, 2). found C T substitution nucleotide position 1192 complementary reference (Gen-Bank accession number: {"type":"entrez-nucleotide","attrs":{"text":"NM_198488.3","term_id":"157311634","term_text":"NM_198488.3"}}NM_198488.3), mutation Korean (7). novel c.1366C>T 2. This is predicted be p.Q444X 1b). remaining six p.Q456X, due 1c). finding common (families 3–8) raised possibility mutational hot spot or founder effect. Based analysis, appears inherited ‘identical descent’ ancestor five these shared extending over 1.8 Mb 1d). 8, different background. Additionally, member. Mutational confirmed neither parent has mutation. Thus, arisen de novo, germline mosaicism one parents cannot excluded. Table 2 Mutations FAM83H FAM83H studied. With results, now (Table Only two mutations, c.1366C>T, more than kindred. (family 1) current study here occurred 3–7) apparent novo another Fig. Lee et al. (8) also p.E415X Identification suggests may high rate, which surprising given relatively small (98,126 bp). Consistent previous findings, raises question whether molecular mechanism haploinsufficiency negative Although terminal messenger RNAs might expected escape nonsense-mediated decay (NMD), there examples humans triggering NMD, notably COL10A1 (9). If mutant transcripts undergo NMD then leads ADHCAI. truncated interfere normal product produce through cluster within 380 amino acid region supportive families, become clearer. FAM83H represents first widely expressed outside developing tooth associated Kim (7) demonstrated expression mouse eye, liver kidney. We verified human kidney, gingiva (data not shown). observed association indicates functions mineralization, its non-mineralized tissues either it does directly function mineralization tissues. Enamel matrix proteins almost completely removed crystallites grow progresses (10). forms AI, significant amounts protein detected fully developed (11). It surprising, therefore, proteases, kallikrein 4 metalloproteinase 20, result phenotypes (4–6). KLK4 recessive phenotypes, suggesting proteinases sufficient Analysis identify obvious homology FAM83 family. Given region, critical development calcification. ADHCAI, responsible majority Turkey. generality effect remains seen.