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James P. Simmer - One of the best experts on this subject based on the ideXlab platform.
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recessive mutations in acp4 cause Amelogenesis Imperfecta
Journal of Dental Research, 2021Co-Authors: Yae Jean Kim, Figen Seymen, James P. Simmer, Yelda Kasimoglu, You Jin Lee, Euisic Cho, J.-w. KimAbstract:Amelogenesis Imperfecta (AI) is an innate disorder that affects the formation and mineralization of the tooth enamel. When diagnosed with AI, one's teeth can be hypoplastic (thin enamel), hypomature (normal enamel thickness but discolored and softer than normal enamel), hypocalcified (normal enamel thickness but extremely weak), or mixed conditions of the above. Numerous studies have revealed the genes that are involved in causing AI. Recently, ACP4 (acid phosphatase 4) was newly found as a gene causing hypoplastic AI, and it was suggested that mutant forms of ACP4 might affect access to the catalytic core or the ability to form a homodimer. In this study, a Korean and a Turkish family with hypoplastic AI were recruited, and their exome sequences were analyzed. Biallelic mutations were revealed in ACP4: paternal (NM_033068: c.419C>T, p.(Pro140Leu)) and maternal (c.262C>A, p.(Arg88Ser)) mutations in family 1 and a paternal (c.713C>T, p.(Ser238Leu)) mutation and de novo (c.350A>G, p.(Gln117Arg)) mutation in the maternal allele in family 2. Mutations were analyzed by cloning, mutagenesis, immunofluorescence, immunoprecipitation, and acid phosphatase activity test. Comparison between the wild-type and mutant ACP4s showed a decreased amount of protein expression from the mutant forms, a decreased ability to form a homodimer, and a decreased acid phosphatase activity level. We believe that these findings will not only expand the mutational spectrum of ACP4 but also increase our understanding of the mechanism of ACP4 function during normal and pathologic Amelogenesis.
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a novel de novo sp6 mutation causes severe hypoplastic Amelogenesis Imperfecta
Genes, 2021Co-Authors: Youn Jung Kim, James P. Simmer, Yejin Lee, Hong Zhang, 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: Jenny Kang, Mine Koruyucu, Hongkeun Hyun, Jan C C Hu, Figen Seymen, Koray Gençay, Teo Jeon Shin, James P. SimmerAbstract: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, James P. Simmer, 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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hypomaturation Amelogenesis Imperfecta caused by a novel slc24a4 mutation
Oral Surgery Oral Medicine Oral Pathology and Oral Radiology, 2015Co-Authors: Curtis R Herzog, Mine Koruyucu, Figen Seymen, Elif Bahar Tuna, Bryan M Reid, James P. SimmerAbstract:In this case report of autosomal recessive pigmented hypomaturation Amelogenesis Imperfecta (AI), we identify a novel homozygous missense mutation (g.165151 T>G; c.1317 T>G; p.Leu436 Arg) in SLC24A4, a gene encoding a potassium-dependent sodium-calcium exchanger that is critical for hardening dental enamel during tooth development.
Figen Seymen - One of the best experts on this subject based on the ideXlab platform.
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recessive mutations in acp4 cause Amelogenesis Imperfecta
Journal of Dental Research, 2021Co-Authors: Yae Jean Kim, Figen Seymen, James P. Simmer, Yelda Kasimoglu, You Jin Lee, Euisic Cho, J.-w. KimAbstract:Amelogenesis Imperfecta (AI) is an innate disorder that affects the formation and mineralization of the tooth enamel. When diagnosed with AI, one's teeth can be hypoplastic (thin enamel), hypomature (normal enamel thickness but discolored and softer than normal enamel), hypocalcified (normal enamel thickness but extremely weak), or mixed conditions of the above. Numerous studies have revealed the genes that are involved in causing AI. Recently, ACP4 (acid phosphatase 4) was newly found as a gene causing hypoplastic AI, and it was suggested that mutant forms of ACP4 might affect access to the catalytic core or the ability to form a homodimer. In this study, a Korean and a Turkish family with hypoplastic AI were recruited, and their exome sequences were analyzed. Biallelic mutations were revealed in ACP4: paternal (NM_033068: c.419C>T, p.(Pro140Leu)) and maternal (c.262C>A, p.(Arg88Ser)) mutations in family 1 and a paternal (c.713C>T, p.(Ser238Leu)) mutation and de novo (c.350A>G, p.(Gln117Arg)) mutation in the maternal allele in family 2. Mutations were analyzed by cloning, mutagenesis, immunofluorescence, immunoprecipitation, and acid phosphatase activity test. Comparison between the wild-type and mutant ACP4s showed a decreased amount of protein expression from the mutant forms, a decreased ability to form a homodimer, and a decreased acid phosphatase activity level. We believe that these findings will not only expand the mutational spectrum of ACP4 but also increase our understanding of the mechanism of ACP4 function during normal and pathologic Amelogenesis.
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alteration of exon definition causes Amelogenesis Imperfecta
Journal of Dental Research, 2020Co-Authors: Yae Jean Kim, Mine Koruyucu, Jenny Kang, Figen Seymen, Yelda Kasimoglu, Merve Bayram, Honghao Zhang, E B Tunaince, Sule Bayrak, Nuray TulogluAbstract:Amelogenesis Imperfecta (AI) is a collection of genetic disorders affecting the quality and/or quantity of tooth enamel. More than 20 genes are, so far, known to be responsible for this condition. In this study, we recruited 3 Turkish families with hypomaturation AI. Whole-exome sequence analyses identified disease-causing mutations in each proband, and these mutations cosegregated with the AI phenotype in all recruited members of each family. The AI-causing mutations in family 1 were a novel AMELX mutation [NM_182680.1:c.143T>C, p.(Leu48Ser)] in the proband and a novel homozygous MMP20 mutation [NM_004771.3:c.616G>A, p.(Asp206Asn)] in the mother of the proband. Previously reported compound heterozygous MMP20 mutations [NM_004771.3:c.103A>C, p.(Arg35=) and c.389C>T, p.(Thr130Ile)] caused the AI in family 2 and family 3. Minigene splicing analyses revealed that the AMELX missense mutation increased exonic definition of exon 4 and the MMP20 synonymous mutation decreased exonic definition of exon 1. These mutations would trigger an alteration of exon usage during RNA splicing, causing the enamel malformations. These results broaden our understanding of molecular genetic pathology of tooth enamel formation.
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candidate gene sequencing reveals mutations causing hypoplastic Amelogenesis Imperfecta
Clinical Oral Investigations, 2019Co-Authors: Youn Jung Kim, Mine Koruyucu, Jenny Kang, Figen Seymen, Teo Jeon Shin, Zang Hee Lee, Elif Bahar Tuna, Sule Bayrak, Nuray Tuloglu, Hongkeun HyunAbstract:Amelogenesis Imperfecta (AI) is a rare hereditary disorder affecting the quality and quantity of the tooth enamel. The purpose of this study was to identify the genetic etiology of hypoplastic AI families based on the candidate gene approach. We recruited three Turkish families with hypoplastic AI and performed a candidate gene screening based on the characteristic clinical feature to find the pathogenic genetic etiology. The candidate gene sequencing of the LAMB3 gene for family 1 revealed a heterozygous nonsense mutation in the last exon [c.3431C > A, p.(Ser1144*)]. FAM20A gene sequencing for families 2 and 3 identified a homozygous deletion [c.34_35delCT, p.(Leu12Alafs*67)] and a homozygous deletion-insertion (c.1109 + 3_1109 + 7delinsTGGTC) mutation, respectively. The candidate gene approach can be successfully used to identify the genetic etiology of the AI in some cases with characteristic clinical features. Identification of the genetic etiology of the AI will help both the family members and dentist understand the nature of the disorder. Characteristic clinical feature can suggest possible genetic causes.
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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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mutations in relt cause autosomal recessive Amelogenesis Imperfecta
Clinical Genetics, 2018Co-Authors: Jung Wook Kim, Mine Koruyucu, Jenny Kang, Figen Seymen, Youn Jung Kim, Hong Zhang, Yelda Kasimoglu, Merve Bayram, Atsushi Ikeda, Chuhua ZhangAbstract:Amelogenesis Imperfecta (AI) is a collection of isolated (non-syndromic) inherited diseases affecting dental enamel formation or a clinical phenotype in syndromic conditions. We characterized three consanguineous AI families with generalized irregular hypoplastic enamel with rapid attrition that perfectly segregated with homozygous defects in a novel gene: RELT that is a member of the tumor necrosis factor receptor superfamily (TNFRSF). RNAscope in situ hybridization of wild-type mouse molars and incisors showed specific Relt mRNA expression by secretory stage ameloblasts and by odontoblasts. Relt-/- mice generated by CRISPR/Cas9 exhibited incisor and molar enamel malformations. Relt-/- enamel had a rough surface and underwent rapid attrition. Normally unmineralized spaces in the deep enamel near the dentino-enamel junction (DEJ) were as highly mineralized as the adjacent enamel, which likely altered the mechanical properties of the DEJ. Phylogenetic analyses showed the existence of selective pressure on RELT gene outside of tooth development, indicating that the human condition may be syndromic, which possibly explains the history of small stature and severe childhood infections in two of the probands. Knowing a TNFRSF member is critical during the secretory stage of enamel formation advances our understanding of Amelogenesis and improves our ability to diagnose human conditions featuring enamel malformations.
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, James P. Simmer, Yejin Lee, Hong Zhang, 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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mutations in relt cause autosomal recessive Amelogenesis Imperfecta
Clinical Genetics, 2018Co-Authors: Jung Wook Kim, Mine Koruyucu, Jenny Kang, Figen Seymen, Youn Jung Kim, Hong Zhang, Yelda Kasimoglu, Merve Bayram, Atsushi Ikeda, Chuhua ZhangAbstract:Amelogenesis Imperfecta (AI) is a collection of isolated (non-syndromic) inherited diseases affecting dental enamel formation or a clinical phenotype in syndromic conditions. We characterized three consanguineous AI families with generalized irregular hypoplastic enamel with rapid attrition that perfectly segregated with homozygous defects in a novel gene: RELT that is a member of the tumor necrosis factor receptor superfamily (TNFRSF). RNAscope in situ hybridization of wild-type mouse molars and incisors showed specific Relt mRNA expression by secretory stage ameloblasts and by odontoblasts. Relt-/- mice generated by CRISPR/Cas9 exhibited incisor and molar enamel malformations. Relt-/- enamel had a rough surface and underwent rapid attrition. Normally unmineralized spaces in the deep enamel near the dentino-enamel junction (DEJ) were as highly mineralized as the adjacent enamel, which likely altered the mechanical properties of the DEJ. Phylogenetic analyses showed the existence of selective pressure on RELT gene outside of tooth development, indicating that the human condition may be syndromic, which possibly explains the history of small stature and severe childhood infections in two of the probands. Knowing a TNFRSF member is critical during the secretory stage of enamel formation advances our understanding of Amelogenesis and improves our ability to diagnose human conditions featuring enamel malformations.
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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, James P. Simmer, 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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a novel amelx mutation causes hypoplastic Amelogenesis Imperfecta
Archives of Oral Biology, 2017Co-Authors: Youngjae Kim, Jenny Kang, Hongkeun Hyun, Teo Jeon Shin, Zang Hee Lee, Youn Jung Kim, Sanghoon Lee, Jung Wook KimAbstract:Abstract Objectives Amelogenesis Imperfecta (AI) is a hereditary genetic defect affecting tooth enamel. AI is heterogeneous in clinical phenotype as well as in genetic etiology. To date, more than 10 genes have been associated with the etiology of AI. Amelogenin is the most abundant enamel matrix protein, most of which is encoded by the amelogenin gene in the X-chromosome (AMELX). More than 16 alternative splicing transcripts have been identified in the murine Amelx gene. The purpose of this study was to identify the genetic cause of an AI family. Materials and methods We recruited a family with hypoplastic AI and performed mutational analysis on the candidate gene based on the clinical phenotype. Results Mutational analysis revealed a missense mutation in exon 6 (NM_182680.1; c.242C > T), which changes a sequence in a highly conserved amino acid (NP_872621.1; p.Pro81Leu). Furthermore, a splicing assay using a minigene displayed that the mutation changed the mRNA splicing repertory. Conclusions In this study, we identified a novel AMELX missense mutation causing hypoplastic AI, and this mutation also resulted in altered mRNA splicing. These results will not only expand the mutation spectrum causing AI but also broaden our understanding of the biological mechanism of enamel formation.
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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 Kyun, James P. SimmerAbstract: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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phenotypic variation in fam83h associated Amelogenesis Imperfecta
Journal of Dental Research, 2009Co-Authors: J T Wright, P. S. Hart, Darrin Simmons, Pjm Crawford, Sylvia A Frazierbowers, K Alexander, Sangwoo T Han, Thomas C. HartAbstract:FAM83H gene mutations are associated with autosomal-dominant hypocalcified Amelogenesis Imperfecta (ADHCAI), which is typically characterized by enamel having normal thickness and a markedly decreased mineral content. This study tested the hypothesis that there are phenotype and genotype associations in families with FAM83H-associated ADHCAI. Seven families segregating ADHCAI (147 individuals) were evaluated. Phenotyping included clinical, radiographic, histological, and biochemical studies, and genotyping was by mutational analysis. Multiple novel FAM83H mutations were identified, including two 2-bp-deletion mutations, the first non-nonsense mutations identified. Craniofacial deviation from normal was more prevalent in the affected individuals. Affected individuals having truncating FAMH3H mutations of 677 or fewer amino acids presented a generalized ADHCAI phenotype, while those having mutations capable of producing a protein of at least 694 amino acids had a unique and previously unreported phenotype a...
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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, M D Michalec, Darrin Simmons, 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, M D Michalec, Darrin Simmons, 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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a nomenclature for x linked Amelogenesis Imperfecta
Archives of Oral Biology, 2002Co-Authors: P. S. Hart, Thomas C. Hart, James P. Simmer, J T WrightAbstract:Abstract Mutations of the X-chromosome amelogenin gene (AMELX) are associated with Amelogenesis Imperfecta (AI) phenotypes (OMIM no. 301200). Currently, 12 different AMELX mutations have been identified in individuals with abnormal enamel characteristic of AI. A notable feature of AI is the variable clinical phenotype, spurring interest in genotype–phenotype correlations. It is important that researchers and clinicians have an informative and reliable means of reporting and communicating these molecular defects. Therefore, the purpose here was to present a systematic nosology for reporting the genomic, cDNA and protein consequences of AMELX mutations associated with AI. The proposed nomenclature adheres to conventions proposed for other conditions and can be adopted for the autosomal forms of AI as the molecular basis of these conditions becomes known.
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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.
Thomas C. Hart - One of the best experts on this subject based on the ideXlab platform.
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phenotypic variation in fam83h associated Amelogenesis Imperfecta
Journal of Dental Research, 2009Co-Authors: J T Wright, P. S. Hart, Darrin Simmons, Pjm Crawford, Sylvia A Frazierbowers, K Alexander, Sangwoo T Han, Thomas C. HartAbstract:FAM83H gene mutations are associated with autosomal-dominant hypocalcified Amelogenesis Imperfecta (ADHCAI), which is typically characterized by enamel having normal thickness and a markedly decreased mineral content. This study tested the hypothesis that there are phenotype and genotype associations in families with FAM83H-associated ADHCAI. Seven families segregating ADHCAI (147 individuals) were evaluated. Phenotyping included clinical, radiographic, histological, and biochemical studies, and genotyping was by mutational analysis. Multiple novel FAM83H mutations were identified, including two 2-bp-deletion mutations, the first non-nonsense mutations identified. Craniofacial deviation from normal was more prevalent in the affected individuals. Affected individuals having truncating FAMH3H mutations of 677 or fewer amino acids presented a generalized ADHCAI phenotype, while those having mutations capable of producing a protein of at least 694 amino acids had a unique and previously unreported phenotype a...
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mmp20 active site mutation in hypomaturation Amelogenesis Imperfecta
Journal of Dental Research, 2005Co-Authors: D Ozdemir, Meltem Ozdemirkaratas, N Piesco, Erhan Firatli, Sun Jin Choi, P. S. Hart, Thomas C. HartAbstract:The Amelogenesis Imperfecta (AI) are a group of clinically and genetically heterogeneous disorders that affect enamel formation. To date, mutations in 4 genes have been reported in various types of AI. Mutations in the genes encoding the 2 enamel proteases, matrix metalloproteinase 20 (MMP20) and kallikrein 4 (KLK4), have each been reported in a single family segregating autosomal-recessive hypomaturation AI. To determine the frequency of mutations in these genes, we analyzed 15 Turkish probands with autosomal-recessive hypomaturation AI for MMP20 and KLK4 gene mutations. No KLK4 mutations were found. A novel MMP20 mutation (g.16250T>A) was found in one family. This missense mutation changed the conserved active-site His226 residue of the zinc catalytic domain to Gln (p.H226Q). Zymogram analysis demonstrated that this missense mutation abolished MMP20 proteolytic activity. No MMP20 mutations were found in the remaining 14 probands, underscoring the genetic heterogeneity of hypomaturation AI.
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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, M D Michalec, Darrin Simmons, 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, M D Michalec, Darrin Simmons, 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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phenotypic diversity and revision of the nomenclature for autosomal recessive Amelogenesis Imperfecta
Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontology, 2004Co-Authors: Mohamad K Nusier, Thomas C. Hart, Othman M Yassin, Afsaneh Samimi, Timothy J WrightAbstract:Abstract Purpose The purpose of this study was to characterize the phenotype in 9 families with autosomal recessive Amelogenesis Imperfecta (ARAI), and to propose a classification system allowing inclusion and delineation of diverse ARAI phenotypes. Study design Nine families with ARAI were evaluated clinically and radiographically. Exfoliated and extracted teeth were examined via light and scanning electron microscopy, with the enamel in one case evaluated by amino acid analysis. Results The 9 families demonstrated diverse ARAI phenotypes including localized hypoplastic, generalized thin hypoplastic, hypocalcified and hypomaturation AI types. Conclusions Some ARAI phenotypes observed in this study and reported in the literature cannot be classified using currently accepted ARAI nomenclature. Therefore, we propose a revised nomenclature permitting both classification of all ARAI clinical forms and inclusion of anticipated molecular-based nomenclature, such as now exists for some X-linked and autosomal dominant AI subtypes.