Identification of a novel mutation (A268G) in exon 8 of the HTR beta gene in a large family with thyroid hormone resistance.
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Alanine↗
Biomedical subjects
M Blayau
Publications and source records attributed to M Blayau.
Identification of a novel mutation in CFTR gene exon 8 (L375F) in a CUAVD phenotype.
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Adult↗
French CF family genotype analysis shows that the R297Q mutation is a rare polymorphism.
The authors describe a cystic fibrosis family genotype analysis showing that the R297Q amino acid change is a rare polymorphism rather than a deleterious mutation as previously reported. Indeed in this family two healthy subjects have the following genotypes: delta F508/R297Q and N1303K/R297Q.
Adult↗
Obstructive azoospermia with agenesis of vas deferens or with bronchiectasia (Young's syndrome): a genetic approach.
Two groups of infertile men with obstructive azoospermia were screened for cystic fibrosis (CF) gene mutations (delta F508, exons 3, 4, 7, 10, 11, 14a, 17b, 19, 20, 21). The first group was composed of 26 patients with congenital agenesis of vas deferens (CAVD). The second group was composed of 12 patients with obstructive azoospermia associated with chronic suppurating respiratory disease (Young's syndrome). Of the group with CAVD, 77% of patients showed at least one mutation in the CF transmembrane conductance regulator (CFTR) gene. The delta F508 mutation occurred most frequently (54%), and the second most frequent mutation to occur was R117H (27%). Six patients were double heterozygotes. In Young's syndrome, no CF mutations were detected. CAVD can be considered as an incomplete clinical form of CF. However, the differences observed in CF mutations between CF and CAVD suggest that they are different disorders resulting from mutations in the same gene. Young's syndrome is a very different clinical entity.
Adult↗
Structural analysis of CFTR gene in congenital bilateral absence of vas deferens.
Congenital bilateral absence of the vas deferens (CBAVD) is found in most males with cystic fibrosis (CF), but this malformation can be observed without any pulmonary or digestive features. We have analyzed 13 exons of the CF gene in a cohort of 25 CBAVD patients. Among the 50 chromosomes studied, 24 mutations were identified: delta F508 (14 cases), R117H (7 cases), R1070W (2 cases), 621 + 1 G --> T (1 case), and A1067V (1 case). Except for delta F508, the most frequent mutations (R117H, R1070W) were not observed in the CF group (109 patients) studied in our laboratory. We discuss the significance of these results.
Adult↗
Proteases.
Proteases are enzymes which are widely distributed in cells and play a key role in protein metabolism. The aim of this paper is to review the classification and nomenclature of proteases, their catalytic mechanisms, the regulation of proteolytic activity and finally the major biological functions of proteases.
Animals↗
Anonymous marker loci within 400 kb of HLA-A generate haplotypes in linkage disequilibrium with the hemochromatosis gene (HFE)
The hemochromatosis gene (HFE) maps to 6p21.3 and is less than 1 cM from the HLA class I genes; however, the precise physical location of the gene has remained elusive and controversial. The unambiguous identification of a crossover event within hemochromatosis families is very difficult; it is particularly hampered by the variability of the phenotypic expression as well as by the sex- and age-related penetrance of the disease. For these practical considerations, traditional linkage analysis could prove of limited value in further refining the extrapolated physical position of HFE. We therefore embarked upon a linkage-disequilibrium analysis of HFE and normal chromosomes from the Brittany population. In the present report, 66 hemochromatosis families yielding 151 hemochromatosis chromosomes and 182 normal chromosomes were RFLP-typed with a battery of probes, including two newly derived polymorphic markers from the 6.7 and HLA-F loci located 150 and 250 kb telomeric to HLA-A, respectively. The results suggest a strong peak of existing linkage disequilibrium focused within the i82-to-6.7 interval (approximately 250 kb). The zone of linkage disequilibrium is flanked by the i97 locus, positioned 30 kb proximal to i82, and the HLA-F gene, found 250 kb distal to HLA-A, markers of which display no significant association with HFE. These data support the possibility that HFE resides within the 400-kb expanse of DNA between i97 and HLA-F. Alternatively, the very tight association of HLA-A3 and allele 1 of the 6.7 locus, both of which are comprised by the major ancestral or founder HFE haplotype in Brittany, supports the possibility that the disease gene may reside immediately telomeric to the 6.7 locus within the linkage-disequilibrium zone. Additionally, hemochromatosis haplotypes possessing HLA-A11 and the low-frequency HLA-F polymorphism (allele 2) are supportive of a separate founder chromosome containing a second, independently arising mutant allele. Overall, the establishment of a likely "hemochromatosis critical region" centromeric boundary and the identification of a linkage-disequilibrium zone both significantly contribute to a reduction in the amount of DNA required to be searched for novel coding sequences constituting the HFE defect.
Alleles↗
[Molecular genetics of hemochromatosis].
Haemochromatosis is an inherited disorder of iron metabolism characterized by a general iron over loading. Without diagnosis and early treatment, it is a serious and potentially fatal disease by cardiac failure or hepatocellular carcinoma in particular. Gene prevalence was estimated at 0.06 in Brittany, so that haemochromatosis may be the most common genetic disease in this area. The biochemical defect of the disease is unknown; only one fact is well established: the iron absorption through duodenal mucosa is excessive. However we don't know if it is a primary event. The gene is also unknown but in 1975 it was located on the short arm of chromosome 6, closely linked to the HLA class I region, less than 1 cM from HLA-A. None of the genes coding for the known iron proteins could be the haemochromatosis gene because of their chromosomal localization. In order to locate this gene with precision, we have used a reverse genetic approach now called positional cloning. Characterization of new polymorphic markers and linkage disequilibrium analysis, have led us to locate the gene within a 350 kb region around HLA-A. We have then searched for all the structural genes in this region. Seven new genes have been so identified and located with precision. A structural analysis of these genes was undertaken to find an eventual abnormality in patients.
Hemochromatosis↗
Anonymous markers located on chromosome 6 in the HLA-A class I region: allelic distribution in genetic haemochromatosis.
Two yeast artificial chromosomes of the HLA class I region were subcloned. Four of the subclones studied displayed restriction polymorphisms that corresponded to six bi-allelic series. Allelic distribution of the anonymous markers was then studied by comparing a control population with a group of patients with familial haemochromatosis. Only one marker presents an unequivocal association with the haemochromatosis gene and is 100 kb centromeric to HLA-A. This association however is not as strong as with HLA-A3. The results suggest two possible locations for the haemochromatosis gene: less than 100 kb centromeric to the HLA-A locus, or on the telomeric side.
Alleles↗
Familial screening for genetic haemochromatosis by means of DNA markers.
Genetic haemochromatosis (HFE) is a frequent and potentially fatal disease. Early phlebotomies may prevent complications. The recessive gene for HFE is unknown but closely linked to the HLA-A locus. No direct test for homozygosity for HFE is currently available, apart from HLA typing within the family of a patient with confirmed HFE. During a reverse genetic approach to identify the gene, we found three anonymous genomic probes (P3, P5, and I.82) derived from previously cloned YACs and physically mapped in the HLA class I region. P3 and P5 probes recognise 3 loci (P3A, P3B, P5) and I.82 one locus about 100 kb from HLA-A. Using five biallelic polymorphisms (I.82/BglII, P3B/EcoRV, P3B/PstI, P5/HindIII, P3A/PstI), we tested 198 HLA typed subjects from the families of 22 haemochromatosis patients. The information from the five polymorphisms was sufficient to identify unequivocally extended restriction haplotypes in all families. The restriction haplotypes cosegregate with the HFE allele and enable identification of genotypically identical sibs in all families studied. The linked DNA markers described in this article avoid the disadvantages of HLA serological typing and can be used in genetic counselling of HFE families.
DNA↗
Dinucleotide repeat polymorphism at the FTHPI locus of chromosome 6.
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Alleles↗
Short-term prednisolone followed by recombinant human alpha-interferon alone or combined with adenine-arabinoside in chronic hepatitis B. A prospective and randomized trial.
Twenty-nine patients with chronic hepatitis B, presenting both hepatitis B surface antigen and hepatitis B virus deoxyribonucleic acid in serum, were studied in a randomized trial treatment consisting of oral prednisolone for 28 days followed 14 days after steroid withdrawal, by either a 55 s.c. injection course of 5 M unit recombinant human alpha-interferon (group 1, 14 patients) or by adenine-arabinoside (for 21 days) combined from the fourteenth day on with the same 55 s.c. injection schedule of interferon (IFN) (group 2, 15 cases). The two groups were well matched with respect to demographic, biochemical, virological and histologic features. Significant side-effects leading to premature discontinuation of interferon were observed in only four cases in group 2 and were always reversible. Efficacy was judged on a mean follow-up period of 17 months. For the whole population, 17 patients (59%) exhibited a sustained serum hepatitis B virus deoxyribonucleic acid disappearance which corresponded to a marked improvement in liver function as demonstrated by a quasi-normalization of their serum transaminase values (ALT with n less than 22 UI/l: 23 +/- 24 vs. 139 +/- 115 before treatment; P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Two polymorphisms at the locus D698 defined by a YAC.
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Cell Line↗
HLA class I gene polymorphism in genetic hemochromatosis.
The authors have studied HLA class I polymorphism in an attempt to identify a genomic marker of the hemochromatosis gene. Five enzymes were used (HindIII, EcoRI, EcoRV, PvuII, and HincII) in 47-106 unrelated patients and 71-91 controls. Both populations were HLA-typed. The relationship between the restriction fragments and HLA-A antigens was considered. Comparison of the two groups revealed a significantly high frequency of one 14 kb EcoRI fragment among the HLA-A3 hemochromatosis patients. The fragment hybridizes to an HLA-A specific probe but not to an HLA-B specific probe, and is associated with the hemochromatosis gene, which is itself associated with HLA-A3.
HLA Antigens↗
Ferritin H gene polymorphism in idiopathic hemochromatosis.
The authors studied the H ferritin restriction polymorphism in 83 hemochromatosis patients and 84 controls as well as in 19 nuclear families. No significant difference was found with the ten restriction enzymes used (HindIII, EcoRI, EcoRV, PvuII, BamHI, PstI, Bg/I, Bg/II, HincII, and TaqI). Hence, the genomic abnormality responsible for idiopathic hemochromatosis is not a major deletion of an H ferritin gene. A higher frequency of one HindIII fragment, although nonsignificant when the number of comparisons made is taken into account, was observed in the patients. This HindIII fragment hybridizes with the H ferritin probe and with a 28 S ribosomal probe, and its segregation with HLA haplotypes (hence its assignment to chromosome 6) is uncertain. Its possible meaning in the expression of the disease is discussed.
Chromosome Mapping↗
Effects of perhexiline maleate on asialo-orosomucoid receptor endocytosis and recycling in HTC cells.
Perhexiline is a lysosomotropic agent which has proved to be very valuable to certain patients suffering from angina pectoris. However long-term administration of the drug may induce hepato- and neuro-toxicity. Using HTC cells (a rat hepatoma-derived cell line) whose plasma membranes were labeled with NaB[3H]4 after oxidation by NaIO4, endocytosis and recycling of labeled asialo-orosomucoid (ASOR) receptors were investigated in the presence of 50 mumols/l perhexiline maleate. The results demonstrate that the drug induces a significant decrease of the rate of both the internalization and the recycling of ASOR receptors. The mechanisms responsible for these effects have not yet been elucidated. However, the current findings may be related to the previously observed inhibitory effect of perhexiline on cellular (Na+, K+)-ATPase and Mg++-ATPase activities. Our findings would then reflect insufficient cellular energy production, resulting from depressed ATP hydrolysis in the presence of perhexiline.
Animals↗
Alpha-L-fucosidase in rat testis during sexual maturity.
alpha-L-fucosidase (EC 3.2.1.51) activity, concentration of testosterone (T), and its metabolite dihydrotestosterone (DHT) were tested in rat testis during the onset of puberty. This study was also carried out in testes of rats treated with 17-beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5-alpha-androstane-3-one (DMAA), an inhibitor of the 5-alpha-reductase-mediated conversion of T into DHT. alpha-L-fucosidase activity in seminiferous tubules of control and DMAA-treated rats was found to be relatively high on the 25th day after birth (approximately 24 units) but decreased and remained relatively constant the following days (approximately 10 units). In contrast, alpha-L-fucosidase activity was nearly undetectable in the immature interstitium of the control rats but sharply increased the following days. A maximum was reached at the 55th day, followed by a rapid decrease. alpha-L-fucosidase activity evolved in parallel with an increase and decrease of DHT concentration. In DMAA-treated rats with DHT levels and an alpha-L-fucosidase activity significantly lower than in the control rats between the 55th and the 65th days, this parallelism existed as well.
Aging↗