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Biomedical subjects

J T Wright

Publications and source records attributed to J T Wright.

At least 55 records · Page 3Linked to original sources
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

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↗
PubMed2000

Unique enamel phenotype associated with amelogenin gene (AMELX) codon 41 point mutation.

Different mutations in the amelogenin gene (AMELX) result in the markedly different enamel phenotypes that are collectively known as amelogenesis imperfecta (AI). We hypothesize that unique phenotypes result from specific genetic mutations. The purpose of this study was to characterize the enamel compositional and structural features associated with a specific AMELX mutation in three families with X-linked AI. We performed mutational analysis by amplifying AMELX exons and sequencing the products. Permanent and primary affected (N = 6) and normal (N = 3) teeth were collected and examined by light, scanning, and transmission electron microscopy. Enamel proteins were evaluated by immunolocalization of amelogenin and amino acid analysis. AI-affected individuals all shared a common AMELX point mutation (C to A change at codon 41). The dental phenotypic findings were remarkably consistent in all affected individuals. The AI enamel was opaque, with numerous prism defects or holes encompassing the entire prism width. Affected crystallites appeared more radiolucent and morphologically less uniform, compared with that of normal enamel. Immunogold labeling with anti-amelogenin antibodies localized amelogenin to the crystallites but not to the inter-crystalline spaces. No immunogold labeling was seen in normal enamel. There was an increased and amelogenin-like protein content in AI enamel (0.95%) compared with normal enamel (0.13%). We conclude that this codon 41 C to A missense point mutation, in a highly conserved region of the AMELX gene, results in a remarkably consistent phenotype.

Amelogenesis Imperfecta↗
PubMed2000

The impact of molecular genetics on oral health paradigms.

As a result of our increased understanding of the human genome, and the functional interrelationships of gene products with each other and with the environment, it is becoming increasingly evident that many human diseases are influenced by heritable alterations in the structure or function of genes. Significant advances in research methods and newly emerging partnerships between private and public sector interests are creating new possibilities for utilization of genetic information for the diagnosis and treatment of human diseases. The availability and application of genetic information to the understanding of normal and abnormal human growth and development are fundamentally changing the way we approach the study of human diseases. As a result, the issues and principles of medical genetics are coming to bear across all disciplines of health care. In this review, we discuss some of the potential applications of human molecular genetics for the diagnosis and treatment of oral diseases. This discussion is presented in the context of the ongoing technological advances and conceptual changes that are occurring in the field of medical genetics. To realize the promise of this new molecular genetics, we must be prepared to foresee the possibilities and to incorporate these newly emergent technologies into the evolving discipline of dentistry. By using examples of human conditions, we illustrate the broad application of this emerging technology to the study of simple as well as complex genetic diseases. Throughout this paper, we will use the following terminology: Penetrance--In a population, defined as the proportion of individuals possessing a disease-causing genotype who express the disease phenotype. When this proportion is less than 100%, the disease is said to have reduced or incomplete penetrance. Polymerase chain reaction (PCR)--A technique for amplifying a large number of copies of a specific DNA sequence flanked by two oligonucleotide primers. The DNA is alternately heated and cooled in the presence of DNA polymerase and free nucleotides, so that the specified DNA segment is denatured, hybridized with primers, and extended by DNA polymerase. MIM--Mendelian Inheritance in Man catalogue number from V. McKusick's Mendelian Inheritance in man (OMIM, 1998).

Chromosome Aberrations↗
PubMed1999

Dental anomalies associated with amelogenesis imperfecta: a radiographic assessment.

Amelogenesis imperfecta, a group of hereditary conditions primarily affecting the enamel, has been associated with dental anomalies, including taurodontism, congenitally missing teeth, delayed eruption, crown resorption, and abnormal enamel density. The purpose of this study was to assess the prevalence of these anomalies in an amelogenesis imperfecta population. The study group consisted of members of 9 unrelated families--22 family members with amelogenesis imperfecta and 13 unaffected family members. Panoramic radiographs were evaluated for taurodontism, congenitally missing teeth, delayed tooth eruption, pathologic dental resorption, pulp calcification, and radiographic enamel density. The prevalence of taurodontism was similar in people with amelogenesis imperfecta and normal people; all of the remaining parameters were more commonly observed in people with amelogenesis imperfecta. The radiographic enamel density was quantitatively reduced in teeth affected by amelogenesis imperfecta in comparison with teeth with normal enamel. These findings suggest that some of the features associated with amelogenesis imperfecta result from abnormal enamel formation (eg, decreased enamel density, crown resorption) whereas others may occur as a result of expression of the genetic mutation in cells other than ameloblasts (eg, abnormal eruption, pulp calcification).

Adolescent↗
PubMed1999

Tricho-dento-osseous syndrome and amelogenesis imperfecta with taurodontism are genetically distinct conditions.

Amelogenesis imperfecta of the hypomaturation-hypoplasia type with taurodontism (AIHHT) is inherited as a highly penetrant autosomal dominant trait. These dental findings are similar to those of another autosomal dominant condition, the tricho-dento-osseous syndrome (TDO), from which AIHHT differs primarily by lack of changes in the hair and bones. TDO is characterized by a highly variable clinical phenotype. While enamel hypoplasia and taurodontism appear to be present in all TDO cases, non-dental features may be absent, with approximately half of TDO cases losing the kinky/curly hair phenotype seen in infancy by adolescence, and in almost 20% of cases, osseous changes are not evident. The genetic basis for AIHHT is unknown and it has been questioned whether AIHHT and TDO are separate conditions or a spectrum of disease. The genetic basis for TDO has recently been identified as a deletion mutation in the distal-less 3 (DLX3) transcription factor gene. To determine if AIHHT and TDO represent variable expression of a common DLX3 gene mutation, allelic mutations of the DLX3 gene, or mutations in DLX7 (the linked paralogue to DLX3 on chromosome 17), we have performed mutational analysis and sequencing studies of the DLX3 and DLX7 genes in three individuals (two affected and one unaffected) from a family with AIHHT. Results of the analysis demonstrate that AIHHT and TDO are not due to a common DLX3 gene mutation. Sequence analyses of the DLX3 and DLX7 genes suggest AIHHT is not due to genetic mutations or polymorphisms in the exons of these genes. These results suggest that AI-HHT and TDO are two genetically distinct conditions.

Abnormalities, Multiple↗
PubMed1998

Dentinogenesis imperfecta: endodontic implications. Case report.

Dentinogenesis imperfecta is a hereditary disorder resulting in defective dentin in both the primary and secondary dentitions. The complications of dentinogenesis imperfecta are difficult to manage and provide a challenge to the dentist. This case report concerns treating an African American patient with dentinogenesis imperfecta who appeared for treatment with endodontic pathosis. It illustrates the need for appropriate and timely restorative treatment to prevent pulpal pathosis. Also demonstrated is the difficulty of endodontically treating dentinogenesis imperfecta teeth because of pulpal obliteration and abnormal dentin mineralization. Early and correct diagnosis of dentinogenesis imperfecta is imperative to enable appropriate preventive interventions and optimal dental treatment. Although pulpal pathosis is rarely reported with dentinogenesis imperfecta, endodontic treatment is occasionally necessary and has a guarded prognosis if initiated after pulp canal obliteration has occurred.

Adult↗
PubMed1998

Prevention of cardiovascular disease in hypertensive patients with normal renal function.

Hypertension is an important risk factor for cardiovascular disease (CVD) in patients with normal renal function. After reviewing over two decades of clinical trial data and an even longer history of epidemiologic data, multiple consensus panels worldwide have made recommendations for the aggressive treatment of hypertension using both lifestyle modification and drug therapy. These data and recommendations provide the basis of the recommendations for preventing CVD in patients with renal disease. Most patients should have elevated blood pressure (BP) lowered to less than 140 mm Hg systolic and less than 90 mm Hg diastolic. Earlier and more aggressive intervention is recommended in high-risk hypertensive patients with risk factors (especially diabetes mellitus) or evidence of target organ damage or clinical CVD. Lifestyle changes are indicated as either initial therapy or concomitant therapy in all hypertensive patients to lower BP and to normalize other CVD risk factors. There is general agreement that clinical outcome data from controlled clinical trials should guide the selection of antihypertensive agents. Currently, these data are only available for thiazide diuretics and beta-blockers for most hypertensive patients with normal renal function and for the dihydropyridine calcium channel blockers in older hypertensive patients with isolated systolic hypertension. However, data may support the use of other agents in hypertensives with selected comorbidity (eg, ACE inhibitors in heart failure, beta-blockers after myocardial infarction, and so forth). However, with only 25% of hypertensive patients controlled to less than 140/90 mm Hg, achieving blood pressure control remains the most important goal in managing hypertension in this population.

Antihypertensive Agents↗
PubMed1998

Identification of a mutation in DLX3 associated with tricho-dento-osseous (TDO) syndrome.

Tricho-dento-osseous syndrome (TDO) is an autosomal dominant disorder characterized by abnormal hair, teeth and bone. The main clinical manifestations of TDO include taurodontism, enamel hypoplasia, kinky, curly hair at birth and increased thickness and density of the cranial bones. These pleiotropic clinical features suggest the role of a developmental gene modulating epithelial-mesenchymal interactions. We recently mapped the TDO locus to chromosome 17q21, a region that includes two members of the distal-less homeobox gene family, DLX3 and DLX7. In this paper we describe genomic cloning and sequencing of both human DLX3 and DLX7 and identification of a 4 bp deletion in human DLX3 which correlates with the TDO phenotype in six families. The observed mutation is predicted to cause a frameshift and premature termination codon, resulting in a functionally altered DLX3. This first report of a human mutation in the DLX genes is consistent with murine studies indicating their important role in the development of hair, teeth and bone.

Abnormalities, Multiple↗
PubMed1998

A common DLX3 gene mutation is responsible for tricho-dento-osseous syndrome in Virginia and North Carolina families.

Tricho-dento-osseous syndrome (TDO) is characterised by a variable clinical phenotype primarily affecting the hair, teeth, and bone. Different clinical features are observed between and within TDO families. It is not known whether the variable clinical features are the result of genetic heterogeneity or clinical variability. A gene for TDO was localised recently to chromosome 17q21 in four North Carolina families, and a 4 bp deletion in the human distal-less 3 gene (DLX3) was identified in all affected members. A previous genetic linkage study in a large Virginia kindred with TDO indicated possible linkage to the ABO, Gc, and Kell blood group loci. To examine whether TDO exhibits genetic heterogeneity, we have performed molecular genetic analysis to determine whether affected members of this Virginia kindred have the DLX3 gene deletion identified in North Carolina families. Results show that affected subjects (n=3) from the Virginia family have the same four nucleotide deletion previously identified in the North Carolina families. A common haplotype for three genetic markers surrounding the DLX3 gene was identified in all affected subjects in the North Carolina and Virginia families. These findings suggest that all people with TDO who have been evaluated have inherited the same DLX3 gene deletion mutation from a common ancestor. The variable clinical phenotype observed in these North Carolina and Virginia families, which share a common gene mutation, suggests that clinical variability is not the result of genetic heterogeneity at the major locus, but may reflect genetic heterogeneity at other epigenetic loci or contributing environmental factors or both.

Abnormalities, Multiple↗
PubMed1998

Enamel structure and composition in the tricho-dento-osseous syndrome.

Tricho-dento-osseous syndrome (TDO) is an autosomal dominant disorder characterized by curly hair, hypoplastic enamel, taurodontism, and dense bone. The purpose of this investigation was to characterize the enamel defects in a TDO population in North Carolina. Twelve TDO teeth and 12 normal teeth were examined. The enamel thickness was decreased in all TDO teeth ranging from having no enamel to about 60% the thickness of normal teeth. Half of the TDO teeth had primarily prismless enamel while the remainder had at least occasional areas of prismatic enamel. TDO enamel crystallites appeared similar to normal crystallites with TEM. The mineral per volume of TDO enamel (n = 9) (68.5%) was significantly less, on average, compared with normal enamel (n = 8) (84.5). The genetic mutation responsible for the TDO phenotype results in alteration of a developmental pathway(s) common to hair, teeth and bone. This further illustrates that these embryologically diverse tissues share common developmental controls at the molecular level.

Abnormalities, Multiple↗
PubMed1997

Analysis of the tricho-dento-osseous syndrome genotype and phenotype.

The tricho-dento-osseous (TDO) syndrome demonstrates kinky curly hair, thin-pitted enamel, taurodontism, and thickening of cortical bone. The purpose of this investigation was to characterize the phenotypic variation of TDO in 3, previously unreported, kindreds and to examine possible candidates for the genomic TDO locus. Thirty-three affected and 20 unaffected individuals were recruited for prospective analysis. Participants were evaluated clinically and photographed by one examiner. Blood was drawn for genetic linkage analyses and radiographs were taken to assess dental and skeletal characteristics. All TDO individuals with teeth had generalized thin and/or pitted enamel hypoplasia. Taurodontism was present in all affected individuals, but was variably expressed. Unique kinky/curly hair at birth was reported in 85% of affected individuals. The curly hair phenotype was retained in 46% of affected individuals after infancy. Thick cranial bones, lack of visible pneumatization of the mastoid process, and/or obliteration of the calvarial diploë was seen in 97% of affected persons compared with 30% of the unaffected individuals. The findings suggest that curly hair at birth, enamel hypoplasia, and taurodontism are highly penetrant yet clinically variable components of TDO. The ABO, Kell, and Gc loci previously suggested to be linked to TDO were excluded as candidates in this TDO population. This investigation characterizes the marked variability in the expression of skeletal, hair, and dental manifestations. The broad range of TDO phenotypes seen in these families, including a variety of skeletal changes, does not support subdividing TDO into multiple subtypes based on subtle phenotypic differences.

Abnormalities, Multiple↗
PubMed1997

The protein composition of normal and developmentally defective enamel.

The development of human enamel involves a complex series of events including the secretion and degradation of a unique extracellular matrix. Ameloblasts progress through a succession of cellular phenotypes executing specialized secretory and regulatory functions. When performing optimally, ameloblasts produce a highly structured and mineralized tissue. Given the elaborate developmental events required for normal enamel formation, it is not surprising that a variety of enamel malformations arise from defects in matrix synthesis, secretion and extracellular processing. Normal matrix secretion and post-secretory processing by ameloblasts can be affected by a variety of hereditary and environmental conditions. These disturbances can result in an abnormal amount and/or composition of matrix proteins, and subsequently, an altered enamel structure and/or mineral content. For example, abnormal matrix removal during enamel maturation apparently contributes to hypomineralization associated with dental fluorosis. Incomplete matrix removal can also occur in several different forms of the hereditary condition amelogenesis imperfects. Specific types of this condition can have retention of substantial enamel protein (e.g. 5% by weight) that is, at least in part, composed of amelogenin and/or its breakdown products. Characterization of the enamel proteins in teeth affected by developmental disturbances can provide insight into the pathogenesis and normal formation of this highly specialized tissue.

Adult↗
PubMed1997

Preadipocyte recruitment in stromal vascular cultures after depletion of committed preadipocytes by immunocytotoxicity.

Glucocorticoids or the glucocorticoid analog dexamethasone (DEX) enhances the differentiation of preadipocytes in the presence of insulin and influences preadipocyte proliferation. The purpose of the present study was to determine if DEX can induce the recruitment of preadipocytes. Using monoclonal antibodies for complement-mediated cytotoxicity, preadipocytes were removed from porcine stromal vascular (S-V) cell cultures. Our experiments demonstrated for the first time that after removal of preadipocytes by cytotoxicity, preadipocytes or fat cells could be induced by DEX or DEX plus insulin but not by insulin alone. However, many more fat cells were induced (258 +/- 15/unit area) when DEX was added with fetal bovine serum (FBS) followed with insulin treatment, compared to DEX with insulin (21.3 +/- 5.1/ unit area) after removal of preadipocytes. Immunocytochemistry with AD-3, a preadipocyte marker, showed that DEX with FBS for 3 days after seeding (i.e., the proliferation phase) produced many more preadipocytes (AD-3 positive, 223 +/- 45/unit area) than FBS alone (10.5 +/- 1.4/unit area). Bromodeoxyuridine (BrdU) incorporation assays demonstrated that the efficiency of DEX with FBS (i.e., during proliferation) was mitosis dependent. Accordingly, we conclude that: porcine S-V cultures contain preadipocytes at different stages of differentiation; and that DEX induced early preadipocyte differentiation depends on mitosis.

Adipocytes↗
PubMed1997

The enamel proteins in human amelogenesis imperfecta.

Amelogenesis imperfecta comprises a unique group of hereditary conditions that result in abnormal enamel development. The purpose of this study was to characterize the enamel proteins in different amelogenesis imperfecta types and to determine if amelogenin, the principal matrix protein in normal developing enamel, was retained. Primary and/or permanent amelogenesis imperfecta teeth were analysed from 11 individuals. Normal teeth served as controls. Thin sections were cut with a diamond blade and enamel was dissected for analysis. The enamel proteins were characterized by amino acid analysis, sodium dodecyl sulphate polyacrylamide gel electrophoresis, and Western blot analysis using antiamelogenin antibodies. An increased protein content was seen in all hypocalcified and hypomaturation amelogenesis imperfecta cases. A slightly increased protein content was seen in two of four hypoplastic amelogenesis imperfecta cases. The enamel protein amino acid composition varied between the different amelogenesis imperfecta types. All three cases of hypomaturation amelogenesis imperfecta enamel showed an increased proline content compared with normal enamel or other amelogenesis imperfecta types. Hypocalcified amelogenesis imperfecta enamel had an increased tyrosine content while the other amino acids were generally similar in amount to normal enamel. Fully developed hypomaturation and hypocalcified amelogenesis imperfecta enamel showed cross-reactivity to antiamelogenin antibodies while normal enamel did not. Although both amelogenesis imperfecta types showed cross-reactivity, the banding patterns on Western blot analyses were markedly different. This investigation provides additional evidence that abnormal post-secretory processing of amelogenin is involved in hypomaturation and hypocalcified amelogenesis imperfecta. Furthermore, these results indicate that amelogenin retention can occur in a variety of amelogenesis imperfecta types. The unique amino acid compositions and distinct enamel protein species seen by electrophoresis and Western blot analyses suggest that different developmental processes might be involved in hypomaturation and hypocalcified amelogenesis imperfecta.

Albumins↗
PubMed1997

Pathophysiology and treatment implications of hypertension in the African-American population.

Regardless of the etiology, hypertension remains a major public health problem in African-Americans and is associated with significant morbidity and mortality. Additional data on the pathophysiology of this disease in this population are needed, as are data on the best therapies to decrease the high complication rate. Because many of the large studies on hypertension have included few African-Americans, recruitment of this ethnic group into clinical trials should be promoted. Further studies into the genetic factors in the pathophysiology of racial differences in hypertension may shed more light on this complex issue.

Antihypertensive Agents↗