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Koray Gençay - One of the best experts on this subject based on the ideXlab platform.
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analyses of mmp20 missense mutations in two families with hypomaturation Amelogenesis imperfecta
Frontiers in Physiology, 2017Co-Authors: Jenny Kang, Mine Koruyucu, Hongkeun Hyun, Figen Seymen, Koray Gençay, Teo Jeon Shin, Jan C C HuAbstract:Amelogenesis imperfecta is a group of rare inherited disorders that affect tooth enamel formation, quantitatively and/or qualitatively. The aim of this study was to identify the genetic etiologies of two families presented with hypomaturation Amelogenesis imperfecta. DNA was isolated from peripheral blood samples of participating family members. Whole exome sequencing was performed using DNA samples from the two probands. Sequencing data was aligned to the NCBI human reference genome (NCBI build 37.2, hg19) and sequence variations were annotated with the dbSNP build 138. Mutations in MMP20 gene were identified in both probands. A homozygous missense mutation (c.678T>A; p.His226Gln) was identified in the consanguineous Family 1. Compound heterozygous MMP20 mutations (c.540T>A, p.Tyr180* and c.389C>T, p.Thr130Ile) were identified in the non-consanguineous Family 2. Affected persons in the family 1 showed hypomaturation AI with dark brown discoloration, which is similar to the clinical phenotype in a previous report with the same mutation. However, the dentition of the proband in the family 2 exhibited slight yellowish discoloration with reduced transparency. The functional analysis showed that the p.Thr130Ile mutant protein had reduced activity of MMP20, while there’s no functional MMP20 in the proband of family 1. These results expand the mutational spectrum of the MMP20 and broaden our understanding of genotype-phenotype correlations in Amelogenesis imperfecta.
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analyses of mmp20 missense mutations in two families with hypomaturation Amelogenesis imperfecta
Frontiers in Physiology, 2017Co-Authors: Youn Jung Kim, Mine Koruyucu, Jenny Kang, Hongkeun Hyun, Figen Seymen, Koray Gençay, Teo Jeon Shin, Zang Hee Lee, Jung Wook KimAbstract:Amelogenesis imperfecta is a group of rare inherited disorders that affect tooth enamel formation, quantitatively and/or qualitatively. The aim of this study was to identify the genetic etiologies of two families presenting with hypomaturation Amelogenesis imperfecta. DNA was isolated from peripheral blood samples obtained from participating family members. Whole exome sequencing was performed using DNA samples from the two probands. Sequencing data was aligned to the NCBI human reference genome (NCBI build 37.2, hg19) and sequence variations were annotated with the dbSNP build 138. Mutations in MMP20 were identified in both probands. A homozygous missense mutation (c.678T>A; p.His226Gln) was identified in the consanguineous Family 1. Compound heterozygous MMP20 mutations (c.540T>A, p.Tyr180* and c.389C>T, p.Thr130Ile) were identified in the non-consanguineous Family 2. Affected persons in Family 1 showed hypomaturation AI with dark brown discoloration, which is similar to the clinical phenotype in a previous report with the same mutation. However, the dentition of the Family 2 proband exhibited slight yellowish discoloration with reduced transparency. Functional analysis showed that the p.Thr130Ile mutant protein had reduced activity of MMP20, while there was no functional MMP20 in the Family 1 proband. These results expand the mutational spectrum of the MMP20 and broaden our understanding of genotype-phenotype correlations in Amelogenesis imperfecta.
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recessive mutations in acpt encoding testicular acid phosphatase cause hypoplastic Amelogenesis imperfecta
American Journal of Human Genetics, 2016Co-Authors: Figen Seymen, Mine Koruyucu, Jenny Kang, Elif Bahar Tuna, Youn Jung Kim, Y. Kasimoglu, Ye Ji Lee, Tak Kim, Hwajung Choi, Koray GençayAbstract:Amelogenesis imperfecta (AI) is a heterogeneous group of genetic disorders affecting tooth enamel. The affected enamel can be hypoplastic and/or hypomineralized. In this study, we identified ACPT (testicular acid phosphatase) biallelic mutations causing non-syndromic, generalized hypoplastic autosomal-recessive Amelogenesis imperfecta (AI) in individuals from six apparently unrelated Turkish families. Families 1, 4, and 5 were affected by the homozygous ACPT mutation c.713C>T (p.Ser238Leu), family 2 by the homozygous ACPT mutation c.331C>T (p.Arg111Cys), family 3 by the homozygous ACPT mutation c.226C>T (p.Arg76Cys), and family 6 by the compound heterozygous ACPT mutations c.382G>C (p.Ala128Pro) and 397G>A (p.Glu133Lys). Analysis of the ACPT crystal structure suggests that these mutations damaged the activity of ACPT by altering the sizes and charges of key amino acid side chains, limiting accessibility of the catalytic core, and interfering with homodimerization. Immunohistochemical analysis confirmed localization of ACPT in secretory-stage ameloblasts. The study results provide evidence for the crucial function of ACPT during Amelogenesis.
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exonal deletion of slc24a4 causes hypomaturation Amelogenesis imperfecta
Journal of Dental Research, 2014Co-Authors: Figen Seymen, Koray Gençay, K E Lee, M Yildirim, Zang Hee Lee, Jongwon KimAbstract:Amelogenesis imperfecta is a heterogeneous group of genetic conditions affecting enamel formation. Recently, mutations in solute carrier family 24 member 4 (SLC24A4) have been identified to cause autosomal recessive hypomaturation Amelogenesis imperfecta. We recruited a consanguineous family with hypomaturation Amelogenesis imperfecta with generalized brown discoloration. Sequencing of the candidate genes identified a 10-kb deletion, including exons 15, 16, and most of the last exon of the SLC24A4 gene. Interestingly, this deletion was caused by homologous recombination between two 354-bp-long homologous sequences located in intron 14 and the 3′ UTR. This is the first report of exonal deletion in SLC24A4 providing confirmatory evidence that the function of SLC24A4 in calcium transport has a crucial role in the maturation stage of Amelogenesis.
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lamb3 mutations causing autosomal dominant Amelogenesis imperfecta
Journal of Dental Research, 2013Co-Authors: Jung Wook Kim, Figen Seymen, Koray Gençay, Teo Jeon Shin, K E Lee, M Yildirim, Elif Bahar Tuna, H K KyunAbstract:Amelogenesis imperfecta (AI) can be either isolated or part of a larger syndrome. Junctional epidermolysis bullosa (JEB) is a collection of autosomal-recessive disorders featuring AI associated with skin fragility and other symptoms. JEB is a recessive syndrome usually caused by mutations in both alleles of COL17A1, LAMA3, LAMB3, or LAMC2. In rare cases, heterozygous carriers in JEB kindreds display enamel malformations in the absence of skin fragility (isolated AI). We recruited two kindreds with autosomal-dominant Amelogenesis imperfecta (ADAI) characterized by generalized severe enamel hypoplasia with deep linear grooves and pits. Whole-exome sequencing of both probands identified novel heterozygous mutations in the last exon of LAMB3 that likely truncated the protein. The mutations perfectly segregated with the enamel defects in both families. In Family 1, an 8-bp deletion (c.3446_3453del GACTGGAG) shifted the reading frame (p.Gly 1149Glufs*8). In Family 2, a single nucleotide substitution (c.C3431A) ...
J T Wright - One of the best experts on this subject based on the ideXlab platform.
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mutation in kallikrein 4 causes autosomal recessive hypomaturation Amelogenesis imperfecta
Journal of Medical Genetics, 2004Co-Authors: P. S. Hart, Thomas C. Hart, Darrin Simmons, M D Michalec, S P Hong, J T WrightAbstract:Serine protease functionality is based on nucleophilic attack of a targeted peptidic bond by a serine. The serine protease superfamily is extremely diverse and includes proteases such as plasminogen, prostatin, hepsin, the kallikrein family ( KLK genes clustered on chromosome 19.13), and a recently discovered cluster of tryptic-like serine proteases located on human chromosome 16p13.1,2 Serine protease mutations have been reported as causative in only a few autosomal recessive human hereditary conditions, which produce diverse pathological conditions.3,4 We report the first human kallikrein mutation and describe its association with a rare autosomal recessive form of Amelogenesis imperfecta. The Amelogenesis imperfectas are a clinically and genetically heterogeneous group of disorders characterised by faulty development of the tooth enamel due to hypoplasia or hypomineralisation.5 The Amelogenesis imperfecta phenotypes vary widely depending on the specific gene involved, the location and type of mutation, and the corresponding putative change at the protein level.6,7 The Amelogenesis imperfecta enamel defects can be broadly divided into hypoplastic (enamel crystallites do not grow to the correct length) and hypomineralised (crystallites fail to grow in thickness or width) phenotypes. The prevalence of Amelogenesis imperfecta varies in different countries (ranging from 1 in 700 in Sweden to 1 in 14 000 in the United States) suggesting allele frequency differences between populations.8–11 Amelogenesis imperfecta can be inherited as an autosomal dominant, autosomal recessive, or X-linked Mendelian trait. While autosomal dominant Amelogenesis imperfecta types are most common in the United States and Europe, autosomal recessive Amelogenesis imperfecta types are more common in the Middle East.8,10,11 Dental enamel is the most highly mineralised tissue in the human body with 85% of its volume occupied by highly organised carbonate substituted hydroxyapatite crystals.12 These crystallites are packed into a highly ordered decussating prism …
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mutation in kallikrein 4 causes autosomal recessive hypomaturation Amelogenesis imperfecta
Journal of Medical Genetics, 2004Co-Authors: P. S. Hart, Thomas C. Hart, Darrin Simmons, M D Michalec, S P Hong, O H Ryu, J T WrightAbstract:Serine protease functionality is based on nucleophilic attack of a targeted peptidic bond by a serine. The serine protease superfamily is extremely diverse and includes proteases such as plasminogen, prostatin, hepsin, the kallikrein family ( KLK genes clustered on chromosome 19.13), and a recently discovered cluster of tryptic-like serine proteases located on human chromosome 16p13.1,2 Serine protease mutations have been reported as causative in only a few autosomal recessive human hereditary conditions, which produce diverse pathological conditions.3,4 We report the first human kallikrein mutation and describe its association with a rare autosomal recessive form of Amelogenesis imperfecta. The Amelogenesis imperfectas are a clinically and genetically heterogeneous group of disorders characterised by faulty development of the tooth enamel due to hypoplasia or hypomineralisation.5 The Amelogenesis imperfecta phenotypes vary widely depending on the specific gene involved, the location and type of mutation, and the corresponding putative change at the protein level.6,7 The Amelogenesis imperfecta enamel defects can be broadly divided into hypoplastic (enamel crystallites do not grow to the correct length) and hypomineralised (crystallites fail to grow in thickness or width) phenotypes. The prevalence of Amelogenesis imperfecta varies in different countries (ranging from 1 in 700 in Sweden to 1 in 14 000 in the United States) suggesting allele frequency differences between populations.8–11 Amelogenesis imperfecta can be inherited as an autosomal dominant, autosomal recessive, or X-linked Mendelian trait. While autosomal dominant Amelogenesis imperfecta types are most common in the United States and Europe, autosomal recessive Amelogenesis imperfecta types are more common in the Middle East.8,10,11 Dental enamel is the most highly mineralised tissue in the human body with 85% of its volume occupied by highly organised carbonate substituted hydroxyapatite crystals.12 These crystallites are packed into a highly ordered decussating prism …
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mutational analysis of x linked Amelogenesis imperfecta in multiple families
Archives of Oral Biology, 2000Co-Authors: S Hart, Carolyn W Gibson, Thomas C. Hart, J T WrightAbstract:Abstract Seven mutations in the amelogenin gene are associated with X-linked Amelogenesis imperfecta. These mutations can produce reductions in the amount of enamel and the degree of mineralization. Two families have been identified from western North Carolina exhibiting features of Amelogenesis imperfecta, characterized by brown enamel in affected males and interposed vertical bands of normal appearing and brown enamel in presumably heterozygous females. Mutational analysis reveals a C–A mutation in exon 6 at codon 41 of the X-chromosomal amelogenin gene, resulting in a pro–thr change in all individuals having the Amelogenesis imperfecta phenotype. This mutation was previously reported in a family with X-linked hypomaturation Amelogenesis imperfecta. There is no known relationship between any of the three families but the presence of similar phenotypes and common mutations suggests they may be distantly related. For individuals from all three families, the haplotype for six highly polymorphic loci flanking the amelogenin gene was determined. A common haplotype was demonstrated among two of the three families, suggesting that the mutation may have been inherited from a common ancestor. The finding that the third family had a distinct haplotype may indicate that the C–A mutation at codon 41 represents a mutational hotspot that occurs with greater frequency than other known amelogenin gene mutations. The phenotype resulting from this mutation was highly consistent in affected male members of the same family and between families.
Figen Seymen - One of the best experts on this subject based on the ideXlab platform.
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DS_10.1177_0022034518824571 – Supplemental material for WDR72 Mutations Associated with Amelogenesis Imperfecta and Acidosis
2019Co-Authors: H. Zhang, Mine Koruyucu, Figen Seymen, Y. Kasimoglu, J.-w. Kim, S. Tinawi, C. Zhang, M.l. Jacquemont, A.r. Vieira, J.p. SimmerAbstract:Supplemental material, DS_10.1177_0022034518824571 for WDR72 Mutations Associated with Amelogenesis Imperfecta and Acidosis by H. Zhang, M. Koruyucu, F. Seymen, Y. Kasimoglu, J.-W. Kim, S. Tinawi, C. Zhang, M.L. Jacquemont, A.R. Vieira, J.P. Simmer and J.C.C. Hu in Journal of Dental Research
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analyses of mmp20 missense mutations in two families with hypomaturation Amelogenesis imperfecta
Frontiers in Physiology, 2017Co-Authors: Jenny Kang, Mine Koruyucu, Hongkeun Hyun, Figen Seymen, Koray Gençay, Teo Jeon Shin, Jan C C HuAbstract:Amelogenesis imperfecta is a group of rare inherited disorders that affect tooth enamel formation, quantitatively and/or qualitatively. The aim of this study was to identify the genetic etiologies of two families presented with hypomaturation Amelogenesis imperfecta. DNA was isolated from peripheral blood samples of participating family members. Whole exome sequencing was performed using DNA samples from the two probands. Sequencing data was aligned to the NCBI human reference genome (NCBI build 37.2, hg19) and sequence variations were annotated with the dbSNP build 138. Mutations in MMP20 gene were identified in both probands. A homozygous missense mutation (c.678T>A; p.His226Gln) was identified in the consanguineous Family 1. Compound heterozygous MMP20 mutations (c.540T>A, p.Tyr180* and c.389C>T, p.Thr130Ile) were identified in the non-consanguineous Family 2. Affected persons in the family 1 showed hypomaturation AI with dark brown discoloration, which is similar to the clinical phenotype in a previous report with the same mutation. However, the dentition of the proband in the family 2 exhibited slight yellowish discoloration with reduced transparency. The functional analysis showed that the p.Thr130Ile mutant protein had reduced activity of MMP20, while there’s no functional MMP20 in the proband of family 1. These results expand the mutational spectrum of the MMP20 and broaden our understanding of genotype-phenotype correlations in Amelogenesis imperfecta.
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analyses of mmp20 missense mutations in two families with hypomaturation Amelogenesis imperfecta
Frontiers in Physiology, 2017Co-Authors: Youn Jung Kim, Mine Koruyucu, Jenny Kang, Hongkeun Hyun, Figen Seymen, Koray Gençay, Teo Jeon Shin, Zang Hee Lee, Jung Wook KimAbstract:Amelogenesis imperfecta is a group of rare inherited disorders that affect tooth enamel formation, quantitatively and/or qualitatively. The aim of this study was to identify the genetic etiologies of two families presenting with hypomaturation Amelogenesis imperfecta. DNA was isolated from peripheral blood samples obtained from participating family members. Whole exome sequencing was performed using DNA samples from the two probands. Sequencing data was aligned to the NCBI human reference genome (NCBI build 37.2, hg19) and sequence variations were annotated with the dbSNP build 138. Mutations in MMP20 were identified in both probands. A homozygous missense mutation (c.678T>A; p.His226Gln) was identified in the consanguineous Family 1. Compound heterozygous MMP20 mutations (c.540T>A, p.Tyr180* and c.389C>T, p.Thr130Ile) were identified in the non-consanguineous Family 2. Affected persons in Family 1 showed hypomaturation AI with dark brown discoloration, which is similar to the clinical phenotype in a previous report with the same mutation. However, the dentition of the Family 2 proband exhibited slight yellowish discoloration with reduced transparency. Functional analysis showed that the p.Thr130Ile mutant protein had reduced activity of MMP20, while there was no functional MMP20 in the Family 1 proband. These results expand the mutational spectrum of the MMP20 and broaden our understanding of genotype-phenotype correlations in Amelogenesis imperfecta.
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recessive mutations in acpt encoding testicular acid phosphatase cause hypoplastic Amelogenesis imperfecta
American Journal of Human Genetics, 2016Co-Authors: Figen Seymen, Mine Koruyucu, Jenny Kang, Elif Bahar Tuna, Youn Jung Kim, Y. Kasimoglu, Ye Ji Lee, Tak Kim, Hwajung Choi, Koray GençayAbstract:Amelogenesis imperfecta (AI) is a heterogeneous group of genetic disorders affecting tooth enamel. The affected enamel can be hypoplastic and/or hypomineralized. In this study, we identified ACPT (testicular acid phosphatase) biallelic mutations causing non-syndromic, generalized hypoplastic autosomal-recessive Amelogenesis imperfecta (AI) in individuals from six apparently unrelated Turkish families. Families 1, 4, and 5 were affected by the homozygous ACPT mutation c.713C>T (p.Ser238Leu), family 2 by the homozygous ACPT mutation c.331C>T (p.Arg111Cys), family 3 by the homozygous ACPT mutation c.226C>T (p.Arg76Cys), and family 6 by the compound heterozygous ACPT mutations c.382G>C (p.Ala128Pro) and 397G>A (p.Glu133Lys). Analysis of the ACPT crystal structure suggests that these mutations damaged the activity of ACPT by altering the sizes and charges of key amino acid side chains, limiting accessibility of the catalytic core, and interfering with homodimerization. Immunohistochemical analysis confirmed localization of ACPT in secretory-stage ameloblasts. The study results provide evidence for the crucial function of ACPT during Amelogenesis.
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exonal deletion of slc24a4 causes hypomaturation Amelogenesis imperfecta
Journal of Dental Research, 2014Co-Authors: Figen Seymen, Koray Gençay, K E Lee, M Yildirim, Zang Hee Lee, Jongwon KimAbstract:Amelogenesis imperfecta is a heterogeneous group of genetic conditions affecting enamel formation. Recently, mutations in solute carrier family 24 member 4 (SLC24A4) have been identified to cause autosomal recessive hypomaturation Amelogenesis imperfecta. We recruited a consanguineous family with hypomaturation Amelogenesis imperfecta with generalized brown discoloration. Sequencing of the candidate genes identified a 10-kb deletion, including exons 15, 16, and most of the last exon of the SLC24A4 gene. Interestingly, this deletion was caused by homologous recombination between two 354-bp-long homologous sequences located in intron 14 and the 3′ UTR. This is the first report of exonal deletion in SLC24A4 providing confirmatory evidence that the function of SLC24A4 in calcium transport has a crucial role in the maturation stage of Amelogenesis.
Barbara Gasse - One of the best experts on this subject based on the ideXlab platform.
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comparative expression of the four enamel matrix protein genes amelogenin ameloblastin enamelin and amelotin during Amelogenesis in the lizard anolis carolinensis
Evodevo, 2015Co-Authors: Barbara Gasse, Jeanyves SireAbstract:In a recent study, we have demonstrated that amelotin (AMTN) gene structure and its expression during Amelogenesis have changed during tetrapod evolution. Indeed, this gene is expressed throughout enamel matrix deposition and maturation in non-mammalian tetrapods, while in mammals its expression is restricted to the transition and maturation stages of Amelogenesis. Previous studies of amelogenin (AMEL) gene expression in a lizard and a salamander have shown similar expression pattern to that in mammals, but to our knowledge there are no data regarding ameloblastin (AMBN) and enamelin (ENAM) expression in non-mammalian tetrapods. The present study aims to look at, and compare, the structure and expression of four enamel matrix protein genes, AMEL, AMBN, ENAM and AMTN during Amelogenesis in the lizard Anolis carolinensis. We provide the full-length cDNA sequence of A. carolinensis AMEL and AMBN, and show for the first time the expression of ENAM and AMBN in a non-mammalian species. During Amelogenesis in A. carolinensis, AMEL, AMBN and ENAM expression in ameloblasts is similar to that described in mammals. It is noteworthy that AMEL and AMBN expression is also found in odontoblasts. Our findings indicate that AMTN is the only enamel matrix protein gene that is differentially expressed in ameloblasts between mammals and sauropsids. Changes in AMTN structure and expression could be the key to explain the structural differences between mammalian and reptilian enamel, i.e. prismatic versus non-prismatic.
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homozygous and compound heterozygous mmp20 mutations in Amelogenesis imperfecta
Journal of Dental Research, 2013Co-Authors: Barbara Gasse, Mathilde Huckert, E Karayigit, Eric Mathieu, A Garret, Supawich Morkmued, S Jung, C Schneider, Loic Vidal, Joseph HemmerleAbstract:In this article, we focus on hypomaturation autosomal-recessive-type Amelogenesis imperfecta (type IIA2) and describe 2 new causal Matrix metalloproteinase 20 (MMP20) mutations validated in two unrelated families: a missense mutation p.T130I at the expected homozygous state, and a compound heterozygous mutation having the same mutation combined with a nucleotide deletion, leading to a premature stop codon (p.N120fz*2). We characterized the enamel structure of the latter case using scanning electron microscopy analysis and microanalysis (Energy-dispersive X-ray Spectroscopy, EDX) and confirmed the hypomaturation-type Amelogenesis imperfecta as identified in the clinical diagnosis. The mineralized content was slightly decreased, with magnesium substituting for calcium in the crystal structure. The anomalies affected enamel with minimal inter-rod enamel present and apatite crystals perpendicular to the enamel prisms, suggesting a possible new role for MMP20 in enamel formation.
Jung Wook Kim - One of the best experts on this subject based on the ideXlab platform.
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a novel de novo sp6 mutation causes severe hypoplastic Amelogenesis imperfecta
Genes, 2021Co-Authors: Youn Jung Kim, Hong Zhang, Yejin Lee, Jisoo Song, Jung Wook KimAbstract:Amelogenesis imperfecta (AI) is a heterogeneous group of rare genetic disorders affecting tooth enamel formation. Here we report an identification of a novel de novo missense mutation [c.817_818delinsAT, p.(Ala273Met)] in the SP6 gene, causing non-syndromic autosomal dominant AI. This is the second paper on Amelogenesis imperfecta caused by SP6 mutation. Interestingly the identified mutation in this study is a 2-bp variant at the same nucleotide positions as the first report, but with AT instead of AA insertion. Clinical phenotype was much more severe compared to the previous report, and western blot showed an extremely decreased level of mutant protein compared to the wild-type, even though the mRNA level was similar.
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analyses of mmp20 missense mutations in two families with hypomaturation Amelogenesis imperfecta
Frontiers in Physiology, 2017Co-Authors: Youn Jung Kim, Mine Koruyucu, Jenny Kang, Hongkeun Hyun, Figen Seymen, Koray Gençay, Teo Jeon Shin, Zang Hee Lee, Jung Wook KimAbstract:Amelogenesis imperfecta is a group of rare inherited disorders that affect tooth enamel formation, quantitatively and/or qualitatively. The aim of this study was to identify the genetic etiologies of two families presenting with hypomaturation Amelogenesis imperfecta. DNA was isolated from peripheral blood samples obtained from participating family members. Whole exome sequencing was performed using DNA samples from the two probands. Sequencing data was aligned to the NCBI human reference genome (NCBI build 37.2, hg19) and sequence variations were annotated with the dbSNP build 138. Mutations in MMP20 were identified in both probands. A homozygous missense mutation (c.678T>A; p.His226Gln) was identified in the consanguineous Family 1. Compound heterozygous MMP20 mutations (c.540T>A, p.Tyr180* and c.389C>T, p.Thr130Ile) were identified in the non-consanguineous Family 2. Affected persons in Family 1 showed hypomaturation AI with dark brown discoloration, which is similar to the clinical phenotype in a previous report with the same mutation. However, the dentition of the Family 2 proband exhibited slight yellowish discoloration with reduced transparency. Functional analysis showed that the p.Thr130Ile mutant protein had reduced activity of MMP20, while there was no functional MMP20 in the Family 1 proband. These results expand the mutational spectrum of the MMP20 and broaden our understanding of genotype-phenotype correlations in Amelogenesis imperfecta.
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lamb3 mutations causing autosomal dominant Amelogenesis imperfecta
Journal of Dental Research, 2013Co-Authors: Jung Wook Kim, Figen Seymen, Koray Gençay, Teo Jeon Shin, K E Lee, M Yildirim, Elif Bahar Tuna, H K KyunAbstract:Amelogenesis imperfecta (AI) can be either isolated or part of a larger syndrome. Junctional epidermolysis bullosa (JEB) is a collection of autosomal-recessive disorders featuring AI associated with skin fragility and other symptoms. JEB is a recessive syndrome usually caused by mutations in both alleles of COL17A1, LAMA3, LAMB3, or LAMC2. In rare cases, heterozygous carriers in JEB kindreds display enamel malformations in the absence of skin fragility (isolated AI). We recruited two kindreds with autosomal-dominant Amelogenesis imperfecta (ADAI) characterized by generalized severe enamel hypoplasia with deep linear grooves and pits. Whole-exome sequencing of both probands identified novel heterozygous mutations in the last exon of LAMB3 that likely truncated the protein. The mutations perfectly segregated with the enamel defects in both families. In Family 1, an 8-bp deletion (c.3446_3453del GACTGGAG) shifted the reading frame (p.Gly 1149Glufs*8). In Family 2, a single nucleotide substitution (c.C3431A) ...