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T C Hart

Publications and source records attributed to T C Hart.

At least 37 records · Page 2Linked to original sources
PubMed2002

Biochemical and mutational analyses of the cathepsin c gene (CTSC) in three North American families with Papillon Lefèvre syndrome.

Papillon Lefèvre syndrome (PLS) is an autosomal recessive disorder characterized by palmoplantar hyperkeratosis and severe periodontitis. The disease is caused by mutations in the cathepsin C gene (CTSC) that maps to chromosome 11q14. CTSC gene mutations associated with PLS have been correlated with significantly decreased enzyme activity. Mutational analysis of the CTSC gene in three North American families segregating PLS identified four mutations, including a novel mutation p.G139R. All mutations were associated with dramatically reduced CTSC protease enzyme activity. A homozygous c.96T>G transversion resulting in a p.Y32X change was present in a Mexican PLS proband, while one Caucasian PLS proband was a compound heterozygote for the p.Y32X and p.R272P (c.815G>C) mutations. The other Caucasian PLS proband was a compound heterozygote for c.415G>A transition and c.1141delC mutations that resulted in a p.G139R and a frameshift and premature termination (p.L381fsX393), respectively. The c.415G>A was not present in more than 300 controls, suggesting it is not a CTSC polymorphism. Biochemical analysis demonstrated almost no detectable CTSC activity in leukocytes of all three probands. These mutations altered restriction enzyme sites in the highly conserved CTSC gene. Sequence analysis of CTSC exon 3 confirmed the previously reported p.T153I polymorphism in 4 of the 5 ethnically diverse populations studied.

Amino Acid Sequence↗
PubMed2002

Amelogenesis imperfecta phenotype-genotype correlations with two amelogenin gene mutations.

Amelogenin, the predominant matrix protein in developing dental enamel, is considered essential for normal enamel formation, but its exact functions are undefined. Mutations in the AMELX gene that encodes for amelogenin protein cause X-linked amelogenesis imperfecta (AI), with phenotypes characterized by hypoplastic and/or poorly mineralized enamel. Eight different AMELX deletion and substitution mutations have been reported to date. The purpose here was to evaluate the genotype and phenotype of two large kindreds segregating for X-linked AI. Phenotypically affected males in family 1 had yellowish-brown, poorly mineralized enamel; those in family 2 had thin, smooth, hypoplastic enamel. Heterozygous females in both kindreds had vertical hypoplastic grooves in their enamel. DNA was obtained from family members; exons 1-7 of AMELX were amplified and sequenced. Mutational analysis of family 1 revealed a single-base-pair change of A-->T at nucleotide 256, resulting in a His-->Leu change. Analysis of family 2 revealed deletion of a C-nucleotide in codon 119 causing a frameshift alteration of the next six codons, and a premature stop codon resulting in truncation of the protein 18 amino acids shorter than the wild-type. To date, all mutations that alter the C-terminus of amelogenin after the 157th amino acid have resulted in a hypoplastic phenotype. In contrast, other AMELX mutations appear to cause predominantly mineralization defects (e.g. the mutation seen in family 1). This difference suggests that the C-terminus of the normal amelogenin protein is important for controlling enamel thickness.

Amelogenesis Imperfecta↗
PubMed2002

A nomenclature for X-linked amelogenesis imperfecta.

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.

Amelogenesis Imperfecta↗
PubMed2002

Identification of a novel cathepsin C mutation (p.W185X) in a Brazilian kindred with Papillon-Lefèvre syndrome.

Papillon-Lefèvre syndrome (PLS) is an autosomal recessive palmoplantar keratoderma caused by cathepsin C (CTSC) gene mutations. This study reports CTSC mutational and enzyme analyses in a consanguineous Brazilian family with PLS, representing the first enzymatic analysis of a Brazilian kinship with PLS. This family segregates a novel PLS-related mutation, p.W185X, that is associated with a complete loss of enzymatic activity.

Amino Acid Sequence↗
PubMed2002

Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy.

INTRODUCTION: Medullary cystic kidney disease 2 (MCKD2) and familial juvenile hyperuricaemic nephropathy (FJHN) are both autosomal dominant renal diseases characterised by juvenile onset of hyperuricaemia, gout, and progressive renal failure. Clinical features of both conditions vary in presence and severity. Often definitive diagnosis is possible only after significant pathology has occurred. Genetic linkage studies have localised genes for both conditions to overlapping regions of chromosome 16p11-p13. These clinical and genetic findings suggest that these conditions may be allelic. AIM: To identify the gene and associated mutation(s) responsible for FJHN and MCKD2. METHODS: Two large, multigenerational families segregating FJHN were studied by genetic linkage and haplotype analyses to sublocalise the chromosome 16p FJHN gene locus. To permit refinement of the candidate interval and localisation of candidate genes, an integrated physical and genetic map of the candidate region was developed. DNA sequencing of candidate genes was performed to detect mutations in subjects affected with FJHN (three unrelated families) and MCKD2 (one family). RESULTS: We identified four novel uromodulin (UMOD) gene mutations that segregate with the disease phenotype in three families with FJHN and in one family with MCKD2. CONCLUSION: These data provide the first direct evidence that MCKD2 and FJHN arise from mutation of the UMOD gene and are allelic disorders. UMOD is a GPI anchored glycoprotein and the most abundant protein in normal urine. We postulate that mutation of UMOD disrupts the tertiary structure of UMOD and is responsible for the clinical changes of interstitial renal disease, polyuria, and hyperuricaemia found in MCKD2 and FJHN.

Alleles↗
PubMed2002

The genome projects: implications for dental practice and education.

Information from the Human Genome Project (HGP) and the integration of information from related areas of study and technology will dramatically change health care for the craniofacial complex. Approaches to risk assessment and diagnosis, prevention, early intervention, and management of craniofacial conditions are and will continue to evolve through the application of this new knowledge. While this information will advance our health care abilities, it is clear that the dental profession will face challenges regarding the acquisition, application, transfer, and effective and efficient use of this knowledge with regards to dental research, dental education, and clinical practice. Unraveling the human genomic sequence now allows accurate diagnosis of numerous craniofacial conditions. However, the greatest oral disease burden results from dental caries and periodontal disease that are complex disorders having both hereditary and environmental factors determining disease risk, progression, and course. Disease risk assessment, prevention, and therapy, based on knowledge from the HGP, will likely vary markedly for the different complex conditions affecting the head and neck. Integration of Information from the human genome, comparative and microbial genomics, proteomics, bioinformatics, and related technologies will provide the basis for proactive prevention and intervention and novel and more efficient treatment approaches. Oral health care practitioners will increasingly require knowledge of human genetics and the application of new molecular-based diagnostic and therapeutic technologies.

Bacteria↗
PubMed2001

Novel COL1A1 mutation (G559C) [correction of G599C] associated with mild osteogenesis imperfecta and dentinogenesis imperfecta.

A genotype-phenotype analysis of a three-generation family segregating for an autosomal-dominant osteogenesis imperfecta (OI) variant is reported here. The family was ascertained through the presentation of a proband concerned about discoloration of her teeth, found to be dentinogenesis imperfecta (DGI). Examination of 36 family members identified 15 individuals with DGI. Linkage studies were performed for genetic markers from candidate intervals known to contain genes responsible for DGI on chromosomes 4q, 7q, and 17q. Conclusive evidence for linkage of DGI was obtained to genetic markers on chromosome 17q21-q22 (DLX-3, Z(max) = 5.34, theta = 0.00). All DGI-affected family members shared a common haplotype, which was not present in individuals without DGI. Haplotype analysis sublocalized the gene to a 5-cM genetic interval that contained the collagen 1 alpha 1 (COL1A1) gene. More than 150 different COL1A1 gene mutations have been associated with various forms of OI, and five of these have been associated with DGI and type IV OI. After excluding these five mutations, mutational analysis was performed on the remaining exons including intron--exon boundaries, which resulted in identification of a Gly559Cys mutation in exon 32, present in all DGI-affected family members. Clinical features segregating with this G559C mutation included hyperextensible joints, joint pain and an increased propensity for bone fractures with moderate trauma. This is the first report of joint pain associated with a COL1A1 mutation and DGI. The mild skeletal features and reduced penetrance of the non-dental findings illustrate the importance of genetic evaluations for families with a history of DGI.

Amino Acid Substitution↗
PubMed2001

Evidence of a founder effect for four cathepsin C gene mutations in Papillon-Lefèvre syndrome patients.

We describe a mutation and haplotype analysis of Papillon-Lefèvre syndrome probands that provides evidence of a founder effect for four separate cathepsin C mutations. A total of 25 different cathepsin C mutations have been reported in 32 families with Papillon-Lefèvre syndrome (PLS) and associated conditions. A characteristic of these findings is the diversity of different cathepsin C mutations that have been identified. To evaluate the generality of cathepsin C mutations, PLS probands representative of five reportedly unrelated Saudi Arabian families were evaluated by mutational and haplotype analyses. Sequence analysis identified two cathepsin C gene mutations: a novel exon 7 G300D mutation was found in the proband from one family, while probands from four families shared a common R272P mutation in exon 6. The R272P mutation has been previously reported in two other non-Saudi families. The presence of the R272P mutation in probands from these four Saudi families makes this the most frequently reported cathepsin C mutation. To distinguish between the presence of a possible founder effect or a mutational hot spot for the R272P mutation, we performed haplotype analysis using six novel DNA polymorphisms that span a 165 kb interval containing the cathepsin C gene. Results of haplotype analysis for genetic polymorphisms within and flanking the cathepsin C gene are consistent with inheritance of the R272P mutation "identical by descent" from a common ancestor in these four Saudi families. Haplotype analysis of multiple PLS probands homozygous for other cathepsin C mutations (W249X, Q286X, and T153I) also supports inheritance of each of these mutations from common ancestors. These data suggest that four of the more frequently reported cathepsin C mutations have been inherited from common ancestors and provide the first direct evidence for a founder effect for cathepsin C gene mutations in PLS. Identification of these six short tandem repeat polymorphisms that span the cathepsin C gene will permit haplotype analyses to determine other founder haplotypes of cathepsin C mutations in additional PLS families.

Amino Acid Substitution↗
PubMed2001

Localization, genomic organization, and alternative transcription of a novel human SAM-dependent methyltransferase gene on chromosome 2p22-->p21.

As part of our studies to identify the gene responsible for hereditary gingival fibromatosis, GINGF (OMIM 135300), we have identified and cloned a novel human gene that contains the highly conserved methyltransferase domain characteristic of S-adenosylmethionine-dependent methyltransferases. We localized this gene (C2orf8 encoding 288L6 SAM-methyltransferase) to chromosome 2p22-->p21 by FISH, and sublocalized it to BAC RP11 288L6 flanked by D2S2238 and D2S2331. Computational analysis of aligned ESTs identified ten exons in the hypothetical C2orf8 gene. Results of RACE analyses in placenta identified multiple transcripts of this gene with heterogeneity at the 5'-UTR. Alternative transcription and tissue specific expression of C2orf8 were detected by RT-PCR and Northern blot analyses. C2orf8 is expressed in a variety of tissues including brain, colon, gingiva, heart, kidney, liver, lung, placenta, small intestine, spleen, and thymus. Open reading frame analysis of the alternative transcripts identified a shared coding region spanning exons 6-10. This ORF consists of 732 nucleotides encoding a putative 244 amino acid protein. Bioinformational searches of both C2orf8 and the putative protein product identified three methyltransferase motifs conserved across many prokaryotic and eukaryotic species. Sequence analyses of C2orf8 excluded coding region mutations as causative of GINGF.

Chromosomes, Human, Pair 2↗
PubMed2000

A unique form of mental retardation with a distinctive phenotype maps to Xq26-q27.

We report a novel X-linked mental retardation (XLMR) syndrome, with characteristic facial dysmorphic features, segregating in a large North Carolina family. Only males are affected, over four generations. Clinical findings in the seven living affected males include a moderate degree of mental retardation (MR), coarse facies, puffy eyelids, narrow palpebral fissures, prominent supraorbital ridges, a bulbous nose, a prominent lower lip, large ears, obesity, and large testicles. Cephalometric measurements suggest that the affected males have a distinctive craniofacial skeletal structure, when compared with normative measures. Obligate-carrier females are unaffected with MR, but the results of cephalometric skeletal analysis suggest craniofacial dysmorphisms intermediate between affected males and normative control individuals. Unaffected male relatives show no clinical or cephalometric resemblance to affected males. The blood-lymphocyte karyotype and the results of DNA analysis for fragile-X syndrome and of other routine investigations are normal. Linkage analysis for polymorphic DNA markers spanning the X chromosome established linkage to Xq26-q27. Maximum LOD scores were obtained at marker DXS1047 (maximum LOD score = 3.1 at recombination fraction 0). By use of haplotype analysis, we have localized the gene for this condition to an 18-cM genetic interval flanked by ATA59C05 and GATA31E08. On the basis of both the clinical phenotype and the mapping data, we were able to exclude other reported XLMR conditions. Therefore, we believe that a unique recessive XLMR syndrome with a distinctive and recognizable phenotype is represented in this family.

Abnormalities, Multiple↗
PubMed2000

Identification of cathepsin C mutations in ethnically diverse papillon-Lefèvre syndrome patients.

INTRODUCTION: Papillon-Lefèvre syndrome (PLS) is an autosomal recessive disorder characterised by palmoplantar keratoderma and severe, early onset periodontitis, which results from deficiency of cathepsin C activity secondary to mutations in the cathepsin C gene. To date, 13 different cathepsin C mutations have been reported in PLS patients, all of which are homozygous for a given mutation, reflecting consanguinity. AIM: To evaluate the generality of cathepsin C mutations in PLS, we studied an ethnically diverse group of 20 unrelated families. METHODS: Mutations were identified by direct automated sequencing of genomic DNA amplified for exonic regions and associated splice site junctions of the cathepsin C gene. Long range PCR was performed to determine the genomic structure of the cathepsin C gene. RESULTS: The cathepsin C gene spans over 46 kb, with six introns ranging in size from 1.6 to 22.4 kb. Eleven novel mutations and four previously reported mutations were identified in affected subjects from 14 families. Missense mutations were most common (9/15), followed by nonsense mutations (3/15), insertions (2/15), and deletions (1/15). Among these 14 probands, two were compound heterozygotes. Affected subjects with transgressions of the dermal lesions onto the knees or elbows or both had mutations in both the pro- and mature regions of the enzyme, although most were in the mature region. CONCLUSION: Mutations in the mature region of cathepsin C were more likely to be associated with the transgressions of the dermatological lesions, although the results were not statistically significant. A comprehensive list of all cathepsin C mutations described to date, representing 25 mutations from 32 families with PLS and related conditions, is also presented.

Cathepsin C↗
PubMed2000

Haim-Munk syndrome and Papillon-Lefèvre syndrome are allelic mutations in cathepsin C.

Of the many palmoplantar keratoderma (PPK) conditions, only Papillon-Lefèvre syndrome (PLS) and Haim-Munk syndrome (HMS) are associated with premature periodontal destruction. Although both PLS and HMS share the cardinal features of PPK and severe periodontitis, a number of additional findings are reported in HMS including arachnodactyly, acro-osteolysis, atrophic changes of the nails, and a radiographic deformity of the fingers. While PLS cases have been identified throughout the world, HMS has only been described among descendants of a religious isolate originally from Cochin, India. Parental consanguinity is a characteristic of many cases of both conditions. Although autosomal recessive transmission of PLS is evident, a more "complex" autosomal recessive pattern of inheritance with phenotypic influences from a closely linked modifying locus has been hypothesised for HMS. Recently, mutations of the cathepsin C gene have been identified as the underlying genetic defect in PLS. To determine if a cathepsin C mutation is also responsible for HMS, we sequenced the gene in affected and unaffected subjects from the Cochin isolate in which both the PLS and HMS phenotypes appear. Here we report identification of a mutation of cathepsin C (exon 6, 2127A--> G) that changes a highly conserved amino acid in the cathepsin C peptide. This mutation segregates with HMS in four nuclear families. Additionally, the existence of a shared common haplotype for genetic loci flanking the cathepsin C gene suggests that affected subjects descended from the Cochin isolate are homozygous for a mutation inherited "identical by descent" from a common ancestor. This finding supports simple autosomal recessive inheritance for HMS in these families. We also report a mutation of the same exon 6 CTSC codon (2126C-->T) in a Turkish family with classical PLS. These findings provide evidence that PLS and HMS are allelic variants of cathepsin C gene mutations.

Alleles↗
PubMed2000

Localisation of a gene for prepubertal periodontitis to chromosome 11q14 and identification of a cathepsin C gene mutation.

Prepubertal periodontitis (PPP) is a rare and rapidly progressive disease of young children that results in destruction of the periodontal support of the primary dentition. The condition may occur as part of a recognised syndrome or may occur as an isolated finding. Both autosomal dominant and recessive forms of Mendelian transmission have been reported for PPP. We report a consanguineous Jordanian family with four members affected by PPP in two nuclear sibships. The parents of the affected subjects are first cousins. We have localised a gene of major effect for PPP in this kindred (Zmax=3.55 for D11S901 at theta=0.00) to a 14 cM genetic interval on chromosome 11q14 flanked by D11S916 and D11S1367. This PPP candidate interval overlaps the region of chromosome 11q14 that contains the cathepsin C gene responsible for Papillon-Lefèvre and Haim-Munk syndromes. Sequence analysis of the cathepsin C gene from PPP affected subjects from this Jordanian family indicated that all were homozygous for a missense mutation (1040A-->G) that changes a tyrosine to a cysteine. All four parents were heterozygous carriers of this Tyr347Cys cathepsin C mutation. None of the family members who were heterozygous carriers for this mutation showed any clinical findings of PPP. None of the 50 controls tested were found to have this Tyr347Cys mutation. This is the first reported gene mutation for non-syndromic periodontitis and shows that non-syndromic PPP is an allelic variant of the type IV palmoplantar ectodermal dysplasias.

Aggressive Periodontitis↗
PubMed2000

Cloning human enamelin cDNA, chromosomal localization, and analysis of expression during tooth development.

Enamelin is the largest protein in the enamel matrix of developing teeth. In the pig, enamelin is secreted as 186-kDa phosphorylated glycoprotein, which is rapidly processed by enamel proteinases into smaller cleavage products. During the secretory stage of enamel formation, enamelin is found among the crystallites in the rod and interrod enamel and comprises roughly 5% of total matrix protein. Although the function of enamelin is unknown, it is thought to participate in enamel crystal nucleation and extension, and the regulation of crystal habit. Here we report the results of enamelin in situ hybridization in a day 1 mouse developing incisor that shows that enamelin is expressed by ameloblasts, but not by odontoblasts or other cells in the dental pulp. The restricted pattern of enamelin expression makes the human enamelin gene a prime candidate in the etiology of amelogenesis imperfecta (AI), a genetic disease in which defects of enamel formation occur in the absence of non-dental symptoms. We have cloned and characterized a full-length human enamelin cDNA and determined by radiation hybrid mapping and fluorescent in situ hybridization (FISH) that the gene is located on chromosome 4q near the ameloblastin gene in a region previously linked to local hypoplastic AI in six families. These findings will facilitate the search for specific mutations in the enamelin gene in kindreds suffering from amelogenesis imperfecta.

Ameloblasts↗