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N D Carter

Publications and source records attributed to N D Carter.

At least 37 records · Page 2Linked to original sources
PubMed2000

A connexin 26 mutation causes a syndrome of sensorineural hearing loss and palmoplantar hyperkeratosis (MIM 148350).

We report a missense mutation in the connexin 26 gene (GJB2) in a family with an autosomal dominant syndrome of hearing loss and hyperkeratosis. The affected family members have high frequency, slowly progressive, bilateral, sensorineural hearing loss and palmoplantar hyperkeratosis. The mutation causes an amino acid substitution (G59A), which may disrupt a reverse turn in the first extracellular loop of connexin 26. Connexin 26 mutations have been reported in syndromes of deafness and palmoplantar keratoderma. These data provide additional evidence for the role of connexin 26 in syndromes of this type.

Amino Acid Substitution↗
PubMed1999

Novel nonsense mutation of the endothelin-B receptor gene in a family with Waardenburg-Hirschsprung disease.

Waardenburg syndrome (WS) comprises sensorineural hearing loss, hypopigmentation of skin and hair, and pigmentary disturbances of the irides. Four types of WS have been classified to date; in WS type IV (WS4), patients additionally have colonic aganglionosis (Hirschsprung disease, HSCR). Mutations in the endothelin-3 (EDN3), endothelin-B receptor (EDNRB), and Sox10 genes have been identified as causative for WS type IV. We screened a family with a combined WS-HSCR phenotype for mutations in the EDNRB locus using standard DNA mutation analysis and sequencing techniques. We have identified a novel nonsense mutation at codon 253 (CGA-->TGA, Arg-->STOP). This mutation leads to a premature end of the translation of EDNRB at exon 3, and it is predicted to produce a truncated and nonfunctional endothelin-B receptor. All affected relatives were heterozygous for the Arg(253)-->STOP mutation, whereas it was not observed in over 50 unrelated individuals used as controls. These data confirm the role of EDNRB in the cause of the Waardenburg-Hirschsprung syndrome and demonstrate that in WS-HSCR there is a lack of correlation between phenotype and genotype and a variable expression of disease even within the same family.

Base Sequence↗
PubMed1999

Interleukin-1 receptor antagonist gene polymorphism and coronary artery disease.

BACKGROUND: Cytokine gene variations are contributory factors in inflammatory pathology. Allele frequencies of interleukin (IL)-1 cluster genes [IL-1A(-889), IL-1B(-511), IL-1B(+3953), IL-1RN Intron 2 VNTR] and tissue necrosis factor (TNF)-alpha gene [TNFA(-308)] were measured in healthy blood donors (healthy control subjects), patients with angiographically normal coronary arteries (patient control subjects), single-vessel coronary disease (SVD), and those with multivessel coronary disease (MVD). METHODS AND RESULTS: Five hundred fifty-six patients attending for coronary angiography in Sheffield were studied: 130 patient control subjects, 98 SVD, and 328 MVD. Significant associations were tested in an independent population (London) of 350: 57 SVD, 191 MVD, and 102 control subjects. IL-1RN*2 frequency in Sheffield patient control subjects was the same as in 827 healthy control subjects. IL-1RN*2 was significantly overrepresented in Sheffield SVD patients (34% vs 23% in patient control subjects); IL-1RN*2 homozygotes in the SVD population (chi2 carriage=8.490, 1 df, P=0.0036). This effect was present though not quite significant in the London population (P=0. 0603). A summary trend test of the IL-1RN SVD genotype data for Sheffield and London showed a significant association with *2 (P=0. 0024). No significant effect of genotype at IL-1RN was observed in the Sheffield or London MVD populations. Genotype distribution analysis comparing the SVD and MVD populations at IL-1RN showed a highly significant trend (P=0.0007) with the use of pooled data. No significant associations were seen for the other polymorphisms. CONCLUSIONS: IL-1RN*2 was significantly associated with SVD. A difference in genetic association between SVD and MVD was also apparent.

Coronary Disease↗
PubMed1999

Relationship between the M235T and G(-6)A polymorphisms of the angiotensinogen gene.

AIMS: Previous studies have reported tight linkage disequilibrium between the T235 and the A(-6) molecular variants of the angiotensinogen gene. This study was designed primarily to ascertain whether a similar relationship exists between the M235 and the G(-6) variants of the gene. We have investigated the degree of agreement between the genotypes of the M235T and the G(-6)A polymorphisms in two ethnic groups. METHODS: Subjects were an heterogeneous group of normotensive and hypertensive subjects of Caucasian (n = 77) and Afro-Caribbean (n = 51) origin. DNA was extracted from whole blood and was genotyped for both the M235T and G(-6)A polymorphisms using PCR-based methods. RESULTS: The distribution frequencies of the MM, MT, and TT genotypes were 0.39, 0.42, and 0.20 in white subjects, and 0.09, 0.17, and 0.74 in black subjects, respectively (chi-square, P < 0.0001). The distribution of AA, GA, and GG genotypes also differed between the two groups as follows: 0.22, 0.48, and 0.30 in white subjects, and 0.82 and 0.18 and 0 in black subjects respectively (chi-square, P < 0.0001). The agreement for TT-AA, MT-GA, and MM-GG was 93%, 91%, and 76% respectively in white and 100%, 67% and 0% respectively in black subjects. CONCLUSIONS: The results indicate ethnic differences in the distribution of both M235T and G(-6)A genotypes. The trend towards a decrease in the degree of agreement in the order of TT-AA > MT-GA > MM-GG suggests that linkage disequilibrium between the M235 and G-6 variant does not mirror that observed with the T235 and A-6 variants. These observations may have significant implications regarding the associations between the G(-6)A polymorphism and hypertension. However, this needs to be further investigated.

Angiotensinogen↗
PubMed1999

Carbonic anhydrase IV activity is localized on the exterior surface of human erythrocytes.

Carbonic anhydrase (CA) cytoplasmic isozymes CA I and CA II were found in human erythrocyte membrane ghosts, when prepared at pH 5.4 and pH 7.4, but not in ghosts prepared at pH 8.2. These findings could indicate that previously reported CA activity of ghosts was owing to contamination by CA I and CA II during the preparation of the ghosts. However, using a sensitive micro-assay, CA activity was also found in ghosts prepared at pH 8.2. This activity constitutes 0.2% of the erythrocytes' total CA-activity, and originates from a membrane-associated isoform of CA, located at the exterior membrane surface. It has immunochemical and kinetic properties like those of the membrane-bound CA IV, previously isolated from kidney, lung and small blood vessels. Its function is possibly to interact with the red cell membrane anionic transport protein, band 3, for the bicarbonate/chloride exchange.

Absorption↗
PubMed1999

Lack of c-kit mutation in familial urticaria pigmentosa.

Somatic mutations within c-kit have been reported in individuals with mastocytoses, including urticaria pigmentosa (UP). We have identified three siblings with UP. We aimed to determine whether the c-kit proto-oncogene was playing a part in the aetiology of UP in these three siblings. Using seven microsatellite repeat markers spanning an 8-cM interval encompassing the c-kit gene we followed the transmission of the c-kit gene in this family. Furthermore, single-strand conformation polymorphism analysis was used to scan exon 17 of the c-kit gene for mutations in genomic DNA of all family members and somatic DNA extracted from skin of the eldest affected sibling, the proband. No mutations were found in exon 17 in either genomic DNA of all family members or somatic DNA of the proband. Patients with UP have been shown to possess somatic mutations of the c-kit gene. However, this locus has been excluded as playing a part in the three siblings examined here in whom a second gene locus must be determining their UP. Therefore, this study emphasizes genetic heterogeneity in UP. Future study to identify primary molecular determinants of UP should include affected sib-pair studies.

Child, Preschool↗
PubMed1999

[Membrane-bound carbonic anhydrase (CA IV) in human corneal epithelium and endothelium].

PURPOSE: Active HCO3- transport through the corneal endothelial cell layer causes a dehydration of the corneal stroma and is thought to be driven by Na/K- and HCO3(-)-dependent ATPase as well as an electro-genic Na/HCO3- cotransport. Transmembrane bicarbonate transport has also been associated with the recently characterised membrane-anchored isoform of carbonic anhydrase (CA IV) in various tissues. We investigated the localisation of CA IV in human fresh and cultured epi- and endothelium at the light- (LM) and electron-microscopic (EM) level. METHODS: Postmortem corneas were obtained within 12 hours of death, stored in formaldehyde and sectioned in paraffin. LM immunohisto-chemistry was performed using the purified gamma-globulin fraction of a polyclonal chicken antibody against CA IV isolated from human kidneys. Epi- and endothelial cell cultures were grown in uncoated flasks under standard conditions and processed both for LM and EM immunohistochemistry using the same antibody. RESULTS: Lightmicroscopy of fresh tissue showed membrane staining for CA IV in the whole circumference of the endothelium. Little staining was also observed in some cells of the basal cell layer of the epithelium. Immunohistochemical staining at the EM level was confined to the cell surface of confluent cultures of both epi- and endothelial cells. CONCLUSION: The localisation of CA IV to the cell surface of fresh and cultured corneal endothelium suggests the presence of a membrane-bound ion exchange mechanism which may be important for HCO3- transport and corneal hydration. Compromising this mechanism by treatment with local carbonicanhydrase inhibitors may be of clinical importance in selected endothelial disease.

Animals↗
PubMed1999

Genetic control of the circulating concentration of transforming growth factor type beta1.

The concentration of transforming growth factor beta (TGF-beta) in plasma has been correlated with the development of several diseases, including atherosclerosis and certain forms of cancer. However, the mechanisms that control the concentration of TGF-beta in plasma are poorly understood. In a study of 170 pairs of female twins (average age 57.7 years) we show that the concentration of active plus acid-activatable latent TGF-beta1 [(a+l) TGF-beta therefore is predominantly under genetic control (heritability estimate 0.54). Single strand conformation polymorphism (SSCP) mapping of the TGF-beta1 gene promoter has identified two single base substitution polymorphisms. The two polymorphisms (G-->A at position -800 bp and C-->T at position -509 bp) are in linkage disequilibrium (correlation coefficient Delta = 0.215, P < 0.01). The C-509T polymorphism is significantly associated with the plasma concentration of (a+l) TGF-beta1, explaining 8.2% of the additive genetic variance of (a+l) TGF-beta1 concentration. It is therefore possible that predisposition to atherosclerosis, bone diseases or various forms of cancer may be correlated with the presence of particular alleles at the TGFB1 locus.

Adult↗
PubMed1999

Association between the C825T polymorphism of the G protein beta3-subunit gene and hypertension in blacks.

A polymorphism (C825T) of the G protein beta3-subunit gene has been associated with low renin hypertension in whites. The aim of this study was to examine the C825T polymorphism in relation to hypertension in a population-based study of black people of African origin who have high prevalence of low renin, salt-sensitive hypertension. A total of 428 men and women, aged 40 to 59 years (270 Caribbeans and 158 West Africans), who took part in a population-based survey were studied. All were blacks and first-generation immigrants. The C825T polymorphism was detected by polymerase chain reaction followed by restriction-enzyme digestion. The prevalence of hypertension (supine blood pressures >/=160 systolic and/or 95 mm Hg diastolic or on drug therapy) was 43%. The distribution of the genotypes (CC, CT, and TT) was in Hardy-Weinberg equilibrium with observed frequencies of 4.0% (n=17), 33.6% (n=144), and 62.4% (n=267), respectively. Allele frequencies were 20.8% for C and 79.2% for T. No difference was detected between Caribbeans and West Africans. A 3-fold higher risk of hypertension was found among the carriers of the T variant both as heterozygotes (odds ratio [OR], 3.43 [95% CI, 0.94 to 12.4]) and homozygotes (OR, 3.87 [95% CI, 1. 09 to 13.8]). The estimate of effect and the blood pressure values in the groups carrying the T variant suggested a dominant model for the T allele. This was confirmed by a significant association between the T allele and hypertension (OR, 3.71 [95% CI, 1.05 to 13. 1]), even when adjusted for age, sex, and body mass index (OR, 4.14 [95% CI, 1.11 to 15.4]). The study shows, for the first time, a high frequency of the 825T allele in black people, and it provides evidence that the T allele may be a susceptibility factor for the development of hypertension in blacks. Given the high frequency of the T allele, even a 2-fold increased risk of hypertension among the carriers of the T allele might account for 44% of the cases of hypertension in blacks.

Adult↗
PubMed1998

Association of hypertension with T594M mutation in beta subunit of epithelial sodium channels in black people resident in London.

BACKGROUND: Liddle's syndrome is a rare inherited form of hypertension in which mutations of the epithelial sodium channel result in increased renal sodium reabsorption. Essential hypertension in black patients also shows clinical features of sodium retention so we screened black people for the T594M mutation, the most commonly identified sodium-channel mutation. METHODS: In a case-control study, 206 hypertensive (mean age 48.0 [SD 11.8] years, men:women 80:126) and 142 normotensive (48.7 [7.4] years; 61:81) black people who lived in London, UK, were screened for T594M. Part of the last exon of the epithelial sodium-channel beta subunit from genomic DNA was amplified by PCR. The T594M variant was detected by single-strand conformational polymorphism analysis of PCR products and confirmed by DNA sequencing. FINDINGS: 17 (8.3%) of 206 hypertensive participants compared with three (2.1%) of 142 normotensive participants possessed the T594M variant (odds ratio [OR]=4.17 [95% CI 1.12-18.25], p=0.029). A high proportion of participants with the T594M variant were women (15 of 17 hypertensive participants and all three normotensive participants), whereas women comprised a lower proportion of the individuals screened (61.2% hypertensive, 57.7% normotensive). However, the association between the T594M variant and hypertension persisted after adjustment for sex and body-mass index (Mantel-Haenszel OR=5.52 [1.40-30.61], p=0.012). Plasma renin activity was significantly lower in 13 hypertensive participants with the T594M variant (median=0.19 ng mL(-1) h(-1)) than in 39 untreated hypertensive individuals without the variant (median=0.45 ng mL(-1) h(-1), p=0.009). INTERPRETATION: Among black London people the T594M sodium-channel beta subunit mutation occurs more frequently in people with hypertension than those without. The T594M variant may increase sodium-channel activity and could raise blood pressure in affected people by increasing renal tubular sodium reabsorption. These findings suggest that the T594M mutation could be the most common secondary cause of essential hypertension in black people identified to date.

Black People↗
PubMed1998

Truncated human endothelin receptor A produced by alternative splicing and its expression in melanoma.

In this study, reverse transcriptase polymerase chain reaction was used to amplify human endothelin receptor A (ETA) and ETB receptor mRNA. A truncated ETA receptor transcript with exons 3 and 4 skipped was found. The skipping of these two exons results in 109 amino acids being deleted from the receptor. The truncated receptor was expressed in all tissues and cells examined, but the level of expression varied. In melanoma cell lines and melanoma tissues, the truncated receptor gene was the major species, whereas the wild-type ETA was predominant in other tissues. A 1.9-kb ETA transcript was identified in melanoma cell lines by Northern blot, which was much smaller than the transcript in heart and in other tissues reported previously (4.3 kb). The cDNA coding regions of the truncated and wild-type ETA receptors were stably transfected into Chinese hamster ovary (CHO) cells. The truncated ETA receptor-transfected CHO cells did not show binding affinity to endothelin 1 (ET-1) or endothelin 3 (ET-3). The function and biological significance of this truncated ETA receptor is not clear, but it may have regulatory roles for cell responses to ETs.

Alternative Splicing↗
PubMed1998

Transforming growth factor-beta1 gene polymorphisms and coronary artery disease.

1. Transforming growth factor-beta1 is a cytokine with a very wide spectrum of biological activities. Previous studies have shown that it is involved in a number of physiological and pathological processes including heart disease. In our study we aimed to scan the transforming growth factor-beta1 locus for polymorphisms and to identify haplotypes significantly associated with a predisposition to coronary atherosclerosis.2. Two patient groups comprising 244 angiographically normal individuals and 655 patients with coronary artery disease were recruited from London and Sheffield. DNA samples from these subjects were screened for mutations in the transforming growth factor-beta1 locus and all subjects were genotyped by a coupled polymerase chain reaction-restriction enzyme digestion method.3. Five polymorphisms have been identified in the transforming growth factor-beta1 gene at positions G-800A, C-509T in the promoter region, Leu10-->Pro, Arg25-->Pro in exon 1 and Thr263-->Ile in exon 5. No significant difference in frequencies for any of the five polymorphisms was found between controls and patients with coronary artery disease. Similarly, there was no correlation between these polymorphisms and hypertension.4. The genotypes of all the individuals participating in the study were assigned to seven main haplotypes of the transforming growth factor-beta1 locus. Based on species comparison data we propose that GCCGC is the ancestral haplotype in humans.5. Our data suggest that these transforming growth factor-beta1 polymorphisms are not associated with coronary artery disease and therefore their presence alone would not be a genetic risk factor for predisposition to coronary artery disease.

Case-Control Studies↗
PubMed1998

Localization of carbonic anhydrase IV in rat and human heart muscle.

We investigated carbonic anhydrase IV (CA IV) in rat and human heart with immunohistochemical methods by both light and electron microscopy. In cryosections that were incubated with anti-CA IV/FITC, the capillaries showed a strong reaction for CA IV. In paraffin and semithin sections treated with anti-CA IV/ABC (avidin-biotin-peroxidase complex) blood vessels, capillaries, and sarcolemma (SL) were positively stained. By staining ultrathin sections with anti-CA IV/immunogold, CA IV could also be demonstrated at the latter two locations, including the specialized sarcolemmal structures intercalated discs, and T-tubules. In addition, by this method CA IV was seen to be associated with the sarcoplasmic reticulum (SR). The absence of immunostaining in SR and/or SL with some techniques probably indicates a problem of accessibility of the antigenic sites. In line with the immunohistochemical results, CA IV mRNA expression was visualized in both endothelial and muscle cells by in situ hybridization histochemistry.

Animals↗
PubMed1998

Methylenetetrahydrofolate reductase polymorphism (C-677T) and coronary artery disease.

1. Many studies have shown that hyperhomocysteinaemia is a risk factor for atherosclerotic vascular disease. A mutation (C-677T) in the gene coding for the methylenetetrahydrofolate reductase (MTHFR) enzyme has been shown to produce a thermolabile form of the enzyme. Homozygosity for this mutation has been correlated with an elevated plasma homocysteine concentration. The present study aimed to determine whether this mutation was a risk factor for coronary artery disease (CAD). This was achieved by comparing the frequency of the C-677T mutation in patients with angiographically proven CAD against angiographically normal patients in two separate U.K. samples. The analysis was repeated with CAD patients split into those with >=99% stenosis of arteries and those without, to establish whether the C-677T mutation could be correlated with severity of CAD.2. Two patient groups were selected from London and Sheffield. The London group comprised 174 cases and 148 controls. The Sheffield group comprised 93 cases and 85 controls. The DNA samples of the patients were genotyped by polymerase chain reaction and restriction enzyme digestion.3. For London the homozygous C-677T frequencies were: 0.07 (controls), 0.09 (CAD without >=99% stenosis) and 0.10 (CAD with >=99% stenosis). For Sheffield the homozygous C-677T frequencies were: 0.08 (controls), 0.10 (CAD without >=99% stenosis) and 0.11 (CAD with >=99% stenosis). No association was found between the C-677T mutation and CAD in our sample geographical groups. Statistical comparison by genotype distribution for 0 VD (no vessel disease, i.e. 0% diameter reduction in all epicardial arteries) versus CAD without >=99% stenosis: London, P=0.19; Sheffield, P=0.53; 0 VD versus CAD with >=99% stenosis: London, P=0. 23; Sheffield, P=0.55.

Aged↗