Characterization of a de novo 43-bp deletion of the Gs alpha gene (GNAS1) in Albright hereditary osteodystrophy.
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Base Sequence↗
Biomedical subjects
R C Trembath
Publications and source records attributed to R C Trembath.
An association between psoriasis and hereditary multiple exostoses. A clue for the mapping of a psoriasis susceptibility gene?
Chronic plaque psoriasis affects approximately 1.6% of the U.K. population. Population, family and twin studies all strongly suggest an important genetic component in the pathogenesis of the disease, although genetic linkage studies have, so far, failed to identify susceptibility genes. We describe a family in which psoriasis cosegregates through three generations with a known autosomal dominant disorder, hereditary multiple exostoses (HME). A major locus for HME has recently been mapped to chromosome 8q. Observations in this family may provide a mapping clue for a psoriasis susceptibility gene.
Adult↗
Albright's hereditary osteodystrophy.
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Adenylyl Cyclases↗
Parental origin of Gs alpha gene mutations in Albright's hereditary osteodystrophy.
Heterozygous mutations of the Gs alpha gene leading to reduced Gs alpha activity have been identified in patients with Albright's hereditary osteodystrophy (AHO). However, AHO may be associated with hormone resistance (pseudohypoparathyroidism type Ia, PHPIa) or a normal response (pseudo-pseudohypoparathyroidism, PPHP). As both disorders may occur within the same family, the relationship between Gs alpha genotype and phenotype remains unresolved. The AHO phenotype may be dependent upon the sex of the parent transmitting the Gs alpha mutation, perhaps through a gene imprinting mechanism. We have used an intragenic Gs alpha FokI polymorphism to determine the parental origin of Gs alpha gene mutations in sporadic and familial AHO. We now show that a de novo G-->A substitution at the exon 5 donor splice junction in a child with PPHP was paternally derived. Furthermore, in a female with PPHP, the Gs alpha abnormality was shown to be of paternal origin, while subsequent maternal processing and transmission resulted in PHPIa in two offspring. As transmission of PPHP has rarely been reported, determining parental origin of the disease allele in sporadic cases may provide insight into the mechanism of hormone resistance in AHO.
Adult↗
Maternally inherited diabetes and deafness is a distinct subtype of diabetes and associates with a single point mutation in the mitochondrial tRNA(Leu(UUR)) gene.
We have recently reported an A to G transition at nucleotide position 3243 in the mitochondrial DNA (mtDNA) tRNA(Leu(UUR)) gene in a large family with non-insulin-dependent diabetes mellitus (NIDDM). Characteristic was its maternal transmission and an associated sensorineural hearing loss. In a screening of a Dutch and French NIDDM population for the presence of the tRNA(Leu(UUR)) mutation we identified two new pedigrees in which NIDDM is present in combination with deafness. The mode of inheritance agrees with a maternal one. This result shows that patients with a phenotype of NIDDM and deafness can be identified within groups of NIDDM patients based on the tRNA(Leu(UUR)) mutation. The same mutation has also been linked to the syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). How the same mutation can give rise to different clinical phenotypes is not clear. We obtained the complete mtDNA sequence from our initial pedigree and identified a number of additional mutations that could confer the phenotype of the tRNA(Leu(UUR)) mutation to diabetes. We examined the presence of these additional, potentially pathogenic mutations in the mtDNA from the two new pedigrees and from a previously described British pedigree. The absence of these mutations in all three pedigrees shows that the tRNA(Leu(UUR)) mutation alone associates with the phenotype of NIDDM and deafness. We conclude that maternally inherited diabetes and deafness is a distinct subtype of diabetes that is associated with a single mitochondrial tRNA(Leu(UUR)) mutation. We propose the abbreviation MIDD for this particular subtype.
Base Sequence↗
Chromosome 11q13 and atopy underlying atopic eczema.
Genetic linkage has been reported between atopic respiratory disease and chromosome site 11q13. We recruited 95 multiplex families through probands with active atopic eczema. Linkage analyses between atopy and markers on 11q13 excluded a major susceptibility locus for atopy in this region. Nor was there significant deviation from the expected proportions of alleles shared by affected sib-pairs. When we analysed families according to parental atopic phenotype, we observed a positive lod score (0.8) in 19 families with unaffected fathers, in contrast to markedly negative scores for other combinations of affected parental phenotype. The possibility of a maternal influence on the inheritance of atopy cannot, therefore, be excluded.
Adult↗
Effect of octreotide on gall stone prevalence and gall bladder motility in acromegaly.
Octreotide therapy in acromegaly is associated with an increased prevalence of gall stones, which may be the result of an inhibition of gall bladder motility. Gall stone prevalence in untreated acromegalic patients relative to the general population is unknown, however, and the presence of gall stones and gall bladder motility in these patients and in acromegalic patients receiving octreotide was therefore examined. Thirty four percent of 39 patients who had taken octreotide for a mean of 20 months had gall stones compared with 16% of 38 patients who had not been treated with octreotide (p < 0.005). In a subgroup of 21 patients studied prospectively over 4 to 18 months, two patients developed stones. No patient had symptoms referrable to their gall stones. In 31 untreated acromegalic patients, the mean fasting gall bladder volume was similar to that in normal subjects. Maximal percentage emptying, however, was impaired (34 v 64%, p < 0.001) and the mean postprandial residual gall bladder volume increased (21.7 v 9.0 ml, p < 0.001). Treatment with octreotide increased the mean postprandial residual volume further to 36.8 ml (p < 0.001). Gall bladder emptying in untreated acromegalic subjects is impaired. Octreotide further increases postprandial residual gall bladder volume and this may be a factor in the increased gall stone prevalence seen in these patients.
Acromegaly↗
Erythromycin induces supranormal gall bladder contraction in diabetic autonomic neuropathy.
Gall bladder motor function is impaired in some patients with diabetes. It has been suggested that the abnormalities of gall bladder motility are confined to those patients with autonomic neuropathy. Erythromycin, a motilin receptor agonist, causes gall bladder contraction in both normal subjects and patients with gall stones with impaired gall bladder emptying. The effect of erythromycin on gall bladder motility in seven patients with diabetes with an autonomic neuropathy, six patients with diabetes without autonomic neuropathy, and 17 normal subjects was studied using ultrasound. There was no significant difference in gall bladder fasting volume between the three groups, but the patients with diabetes with autonomic neuropathy had impaired postprandial gall bladder emptying compared with normal subjects (percentage emptied (SEM) 40 (10.3)% v 64 (2.8)%, p < 0.01) and those with autonomic neuropathy (48 (7.7)%, NS). Erythromycin produced a dramatic reduction in gall bladder fasting volume in patients with diabetes with an autonomic neuropathy, compared with either normal subjects or patients with diabetes without autonomic neuropathy (percentage reduction 62 (4.6)% in patients with autonomic neuropathy, v 37 (17.6)% in those without autonomic neuropathy, and 26 (7.3)% in the normal subjects, (p < 0.02) and returned gall bladder emptying to normal in all patients with impaired emptying. The pronounced effect of erythromycin in diabetic autonomic neuropathy suggests denervation supersensitivity and that the action of erythromycin on the gall bladder is neurally modulated.
Adult↗
Diabetes mellitus associated with a pathogenic point mutation in mitochondrial DNA.
Family studies of diabetes mellitus (DM) show that patients are more likely to have affected mothers than affected fathers. Since the inheritance of mitochondrial (mtDNA), unlike nuclear DNA, is exclusively maternal, could it be that defect(s) in mtDNA account for some cases of DM? Such defects have been associated with rare neurological syndromes, in some of which DM has been an accompanying feature. We have looked for glucose intolerance and for a previously known point mutation of mtDNA in a family, some of whose members have a multisystem disorder with DM but not neurological involvement. DNA samples were obtained from fourteen family members. The point mutation (affecting position 3243 in the tRNA leucine mitochondrial gene) was found in all three diabetic patients and post mortem tissues in the proband; it was also found in seven offspring of female patients. It was not found in the two children of the male proband. The contribution of this mutation to DM in general is not known but clinicians ought to be aware of the possibility, especially in families with multisystem disease and maternal transmission.
Adult↗
Effect of oral erythromycin on gallbladder motility in normal subjects and subjects with gallstones.
The action of the motilin receptor agonist erythromycin on human gallbladder contraction, measured by ultrasound, both in normal subjects and those with gallstone disease was studied. In 17 normal subjects, oral erythromycin administration (500 mg; vs. placebo) reduced fasting gallbladder volume at 2 hours (26.2 vs. 19.0 mL; P less than 0.001), and postprandial residual gallbladder volume (9.0 vs. 4.4 mL; P less than 0.001) and the rate constant of gallbladder emptying following the meal was significantly increased. Erythromycin also reduced fasting and residual gallbladder volumes in 13 patients with gallstone disease: in 6 who underwent cholecystolithotomy, fasting volume was 29.5 vs. 22.3 mL (P less than 0.05) and residual volume was 17.7 vs. 6.5 mL (P less than 0.05), and in 7 with gallstones in situ, fasting volume was 23.8 vs. 14.3 mL (P less than 0.05) and residual volume was 17.2 vs. 5.0 mL (P less than 0.05). In 7 of 8 subjects with gallstones and impaired gallbladder emptying, the gallbladder emptied normally following administration of erythromycin, and in 3 of the other 5 gallstone subjects gallbladder emptying was increased. In 6 normal subjects given erythromycin three times weekly for 1 month, the effect was maintained (fasting volume, 18.8 mL, P less than 0.001; residual volume, 3.7 mL, P less than 0.001). Oral erythromycin significantly reduces fasting and postprandial residual gallbladder volumes in both normal subjects and subjects with gallstones and reverses the gallbladder motility defect found in a proportion of subjects with gallstones. This effect is maintained for a month in normal subjects.
Administration, Oral↗
Nesidioblastosis: evidence for autosomal recessive inheritance.
The risk of recurrence of nesidioblastosis is unclear. Thirty patients from 28 families were studied; the marriages were consanguineous in five families. The ratio of subsequent affected to unaffected siblings was similar to that of an autosomal recessive condition and the sex ratio was close to 1.
Female↗
Anticardiolipin antibody levels in diabetic subjects with and without coronary artery disease.
Moderate (greater than 20 units) and high (greater than 80 units) IgG anticardiolipin antibody (aCL) titres are strongly predictive for recurrent thrombosis and early myocardial infarction in non-diabetic subjects. We have tested the hypothesis that the excess risk of myocardial infarction in diabetic subjects relates to the presence of aCL by measuring the frequency and titre of aCL in two groups of diabetic subjects and in 2500 healthy controls. One non-diabetic subject (0.04%) had low (5-20 units) IgG aCL titres. Seven out of 126 diabetics without cardiovascular disease (5.6%) and 9 out of 79 diabetics who were either myocardial infarction survivors or who had angiographically-proven coronary artery disease (11.4%) had low aCL titres (P less than 0.01 for comparison of either diabetic group with controls, and P less than 0.1 for comparison between diabetic groups). One subject in each diabetic group, but no non-diabetics, had moderate IgM aCL titres. No subjects had high aCL titres. Diabetics have an increased frequency of low aCL titres which may relate to macrovascular disease. Macrovascular disease in diabetics is not associated with moderate or high aCL titres.
Cardiolipins↗
Linkage analysis of the human insulin receptor gene in type 2 (non-insulin-dependent) diabetic families and a family with maturity onset diabetes of the young.
The possibility of linkage between the human insulin receptor gene locus and diabetes was examined in three Type 2 (non-insulin-dependent) diabetic families and one family with maturity onset diabetes of the young. Insulin receptor gene haplotypes were established using BglII, Rsal and Sstl restriction enzyme digests of genomic DNA from all available family members. The digested DNA was subjected to agarose gel electrophoresis, Southern blotted, and hybridised to 32P-labelled human insulin receptor gene cDNA. In the pedigree with maturity onset diabetes of the young, formal linkage analysis allowed exclusion of close linkage between the insulin receptor locus and diabetes (logarithm of the odds for linkage versus non-linkage was -5.35 at recombination fraction of 0.01). This confirms the absence of linkage between insulin receptor and diabetes which has been reported in two similar pedigrees. In the three Type 2 diabetic families there were a minimum of 4 recombinants between the insulin receptor locus and diabetes, which makes a direct role for insulin receptor defects unlikely. The importance of using realistic estimates of penetrance when performing linkage analysis in a disease with a late age of onset is emphasised. In contrast to the one previous linkage analysis study of the insulin receptor gene, no specific association of diabetes with the rare Sst1 S1(-) allele was observed in either the maturity onset diabetes of the young or the Type 2 diabetic families.
Adolescent↗
Genetic variants of the insulin receptor in type II (non-insulin dependent) diabetes mellitus.
DNA variation related to the insulin receptor gene was studied with the restriction endonucleases Sst 1 and Bgl II. These identified 4 alleles, termed S1 (5.3 kilobases), S2 (5.8 kilobases), B1 (23.4 kilobases) and B2 (20.0 kilobases). Random association between these two insulin receptor polymorphisms was found in all of the study groups. The frequencies of genotypes possessing the S2 allele in Caucasian controls (n = 54), race matched non-insulin dependent diabetics (n = 56) and insulin dependent diabetics (n = 34) were 0.06, 0.18 and 0.04 respectively (p less than 0.01 for NIDDM versus IDDM or controls by chi-squared test). There were no significant differences in frequencies of genotypes with the B1 or B2 alleles amongst these three groups. The S2 allele or adjacent loci may provide a useful genetic marker for NIDDM.
Alleles↗
Deoxyribonucleic acid polymorphism of the apoprotein AI-CIII-AIV gene cluster and coronary heart disease in non-insulin-dependent diabetes.
The prevalence of an uncommon allelic variant (S2) of the apoprotein AI-CIII-AIV gene cluster was determined in non-insulin-dependent diabetics with or without evidence of coronary heart disease and in controls. Frequencies of the S2 allele were 14% for diabetics with coronary heart disease compared with 2% for non-diabetics with no clinical evidence of occlusive vascular disease. No subject with the S2 allele was detected among a further group of matched diabetics without clinical features of macrovascular disease. The results suggest that a genetic component contributes to the susceptibility to coronary heart disease in non-insulin-dependent diabetics. Whether the observed deoxyribonucleic acid variant is aetiological for atherosclerosis or in linkage disequilibrium with other atherogenic loci on chromosome 11 remains to be clarified.
Alleles↗
DNA polymorphisms of the insulin receptor gene and non-insulin-dependent diabetes mellitus.
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DNA↗
Genetic mechanisms and mental retardation.
The past five years have witnessed rapid and apparently relentless progress in the delineation of the genetic basis of disorders associated with mental retardation. Each gene discovery has a new story to tell but inevitably generates further questions. For the clinical geneticist and, perhaps more importantly, for patients and their families, many of these recent discoveries have yielded information which has immediate implications for diagnostic testing, family and population screening and prenatal testing. Many of the ethical issues consequent upon the rapid progress are only now being addressed. This article highlights a number of disorders whose molecular genetic basis has recently been further characterised. Brain development and maintenance of neurological networks provide the unifying theme; the genetic defects are disparate and each of their mechanisms appears to be novel.
Chromosome Deletion↗