Search PubMed⌕ Search

Biomedical subjects

J Yaouanq

Publications and source records attributed to J Yaouanq.

34 records · Page 2Linked to original sources
PubMed1992

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↗
PubMed1992

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↗
PubMed1990

Percent transferrin saturation in segregating hemochromatosis.

The segregation of genetic hemochromatosis was analyzed by using percent transferrin saturation (TS) as a phenotypic marker of the disease. Homozygotes for the disease were readily discernable with the added information provided by the quantitative indicator. However, there was no evidence of partial expression of TS abnormalities in heterozygotes, contrary to previous studies.

Adult↗
PubMed1990

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↗
PubMed1990

Serum ferritin as a marker of affection for genetic hemochromatosis.

A bivariate segregation analysis of genetic hemochromatosis with serum ferritin concentration was undertaken to examine the pleiotropic effect of the hemochromatosis locus on each of the two phenotypes, in an ascertained sample of families from Brittany, France. The gene was recessive with respect to both phenotypes, and the estimated gene frequency in the general population was 0.054. Although the ferritin concentration was corrected for the linear relationship with age among controls, there was a residual correlation with age among male family members, consistent with the progressive increase in body iron stores among hemochromatosis homozygotes. This genotype-specific relationship with age illustrates the importance of incorporating interaction effects into analytic models, and suggests that even as a better indicator of progress of disease, rather than liability to disease, serum ferritin concentration serves well to distinguish hemochromatosis homozygotes from alternate genotypes in a family study.

Adult↗
PubMed1990

Combined segregation and linkage analysis of genetic hemochromatosis using affection status, serum iron, and HLA.

Characterizing the distribution of parameters of iron metabolism by hemochromatosis genotype remains an important goal vis-à-vis potential screening strategies to identify individuals at genetic risk, since a specific marker to detect the abnormal gene has not been identified as yet. In the present investigation, we analyze serum iron values in ascertained families using a method which incorporates both segregation of the clinical affection status and the HLA linkage information to identify the underlying genotypes. The analysis is performed using an extension of the model presented by Bonney et al., comprising regressive models for segregation analysis and the multipoint linkage strategy implemented in LINKAGE. The gene was found to be completely recessive with respect to both clinical manifestations and serum iron abnormalities, with significant differences in expression by sex. Clinical manifestations were present for all male homozygotes in this data set, suggesting that the recessive hemochromatosis genotype is fully penetrant at all ages in males. This was not the case for younger females. Significant genotype-specific age and sex effects were found for serum iron values. It is interesting that deletion of the HLA marker information did not affect our ability to resolve the genetic model when we analyzed a bivariate phenotype. This serves as a reminder that a search for relevant biological markers can be equally important in discerning the genetic etiology of a disease trait, as a search for linked genetic markers.

Age Factors↗
PubMed1989

Genetic hemochromatosis: distribution analysis of six laboratory measures of iron metabolism.

Six laboratory measures of iron metabolism were studied in a control sample, and a family sample was ascertained on the basis of probands with clinically diagnosed genetic hemochromatosis. The respective distribution of each variable evidenced a mixture of components, presumably arising from the segregation of an HLA-linked locus for hemochromatosis. There were significant differences in the distributional characteristics with respect to sex and genotype-specific variances. These aspects of the data have important implications for subsequent segregation and linkage analyses, which traditionally assume homoscedasticity and homogeneity of the genetic effect.

Deferoxamine↗
PubMed1989

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↗
PubMed1989

Segregation of genetic hemochromatosis indexed by latent capacity of transferrin.

A genetic analysis of the segregation of hereditary hemochromatosis, indexed by the measurement of latent capacity of transferrin (LCAP), was undertaken in an ascertained sample of 147 pedigrees from Brittany, France. There were no mean differences by sex in the distribution of LCAP in the control sample, although in the family data there was a higher representation of males with low values than of females with low values, consistent with the higher proportion of affected males. The results of bivariate segregation analysis revealed no systematic evidence for heterozygous expression either in the biochemical domain of LCAP abnormalities or in increased liability to overt symptomatic disease. Joint consideration of the quantitative variable with hemochromatosis affection status allowed clear resolution of a recessive single-gene inheritance pattern in these families.

Adult↗
PubMed1987

A study of 609 HLA haplotypes marking for the hemochromatosis gene: (1) mapping of the gene near the HLA-A locus and characters required to define a heterozygous population and (2) hypothesis concerning the underlying cause of hemochromatosis-HLA association.

We compared 609 haplotypes carrying the idiopathic hemochromatosis allele with 475 control haplotypes. Four haplotypes were more frequent in hemochromatosis: A3, B7 (actually A3, CW., B7, Bfs, DR2); A3, B14 (actually A3, CW., B14, BfF, DRW6); A11, B35; and A11, B5. The linkage disequilibrium for A3, B7 and A3, B14 (and probably also for A11, B5) was undeniably stronger in hemochromatosis than in controls. Two haplotypes--A3, B12 and A3, B15--were more frequent in hemochromatosis, without linkage disequilibrium. Four haplotypes in linkage disequilibrium in hemochromatosis--i.e., A2, B12; A1, B8; A9, B7; and A29, B12--were also found to have the same frequency and strength of linkage in controls. The dual observation (1) that haplotypes carrying A3 without either B7 or B14 were highly significantly more frequent in hemochromatosis than in controls and (2) that haplotypes carrying B7 or B14 but not A3 had the same frequency in hemochromatosis and controls led to the formal conclusion that only A3 is an independent marker for the hemochromatosis allele, B7 and B14 being involved only owing to the haplotypic mode of marking; the hemochromatosis allele can thus be mapped closer to locus A than to locus B. Our findings fit well with the hypothesis that the hemochromatosis mutation was a rare if not unique event that produced an ancestral HLA marking that was subsequently modified by recombinations and geographical scattering due to migrations.

Alleles↗
PubMed1986

DNA polymorphism related to the idiopathic hemochromatosis gene: evidence in a recombinant family.

The metabolic error involved in idiopathic hemochromatosis, as well as the underlying genetic defect remain unknown. It has, however, been recently shown that this genetic lesion occurs at a locus linked to the major histocompatibility complex, probably close to the HLA-A locus, and that the disease is recessively transmitted. Therefore, in a family where one subject has idiopathic hemochromatosis his HLA-identical siblings should also be affected. We present here the restriction polymorphism with two MHC class I probes and one DR beta probe in an exceptional family with three HLA-identical siblings: one (the proband) has a major form of idiopathic hemochromatosis, while the other two are free of any clinical or biochemical signs of the disease. The restriction patterns observed after DNA digestion by enzymes EcoRI, EcoRV, BglII, BamHI, PvuII, TaqI, HincII, and HindIII led to the conclusion that one of the proband's chromosome 6 had undergone two alterations: one, a deletion in the DR region, was revealed by missing fragments all correlated with DR5; the other was an unbalanced cross-over or a genetic conversion in the MHC class I region. This latter alteration was revealed by modifications in the patterns of high molecular weight HindIII bands which hybridize with probe pHLA2 and also by the absence of a HindIII fragment of 7.4 kb hybridized by another class I probe. This latter alteration most likely involved the hemochromatosis gene and could be the first step toward a molecular approach to this gene.

Adult↗
PubMedDate not supplied

Renal scintigraphy in insulin-dependent diabetes mellitus: early glomerular and urologic dysfunction.

Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured by intravenous injection of 99mTc-diethylenetriaminepentaacetic acid (DTPA) and 131I-Hippuran in 115 insulin-dependent diabetic patients with albumin excretion rates (AER) less than 200 micrograms/min, and in 45 normal subjects. Separate kidney function and urinary elimination were estimated by renography. GFR was increased in the diabetic patients (152 +/- 24 ml/min/1.73 m2 vs. 128 +/- 15) and correlated significantly with RPF (r = 0.5; p less than 10(-9)). No relationship was found between GFR and the duration of diabetes, blood glucose, HbA1c, or AER. Fifty patients were hyperfiltering with RPF and filtration fraction higher than those in the normofiltering group. Slow intrarenal or pyeloureteral elimination, either unilateral or bilateral, was observed in 3 controls and 60 diabetic subjects (24 hyperfiltering; 36 normofiltering) and did not disappear with the patient in the standing position. In these 60 patients, mean age, duration of diabetes, blood glucose, HbA1c, 24 h albumin excretion rate, and frequency of peripheral or autonomic neuropathy did not differ from patients with normal scintigraphy; GFR was lower in the group with slow elimination, but not significantly so. 99mTc-DTPA renal uptake was symmetric in all the controls; asymmetric renal uptake with asymmetric GFR was observed in 13 patients (7 hyperfiltering; 6 normofiltering) and often associated with slower elimination. No evidence for renal stenotic atheroma or parenchymatous disease was found on the angiopyeloureterography. The results suggest that incipient uropathy is a very common phenomenon that occurs irrespective of glomerular dysfunction.

Diabetes Mellitus, Type 1↗
PubMedDate not supplied

[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 serous 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.

Chromosome Inversion↗