Homozygous case of hereditary coproporphyria.
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Adult↗
Biomedical subjects
B Grandchamp
Publications and source records attributed to B Grandchamp.
The red blood cell band 3 variant (band 3Biceêtrel:R490C) associated with dominant hereditary spherocytosis causes defective membrane targeting of the molecule and a dominant negative effect.
Hereditary spherocytosis (HS), a common human inherited haemolytic anaemia, is associated with partial deficiency of different erythrocyte membrane proteins. In a subset of dominant HS, a partial membrane expression deficiency of band 3, the erythrocyte anion exchanger (AE1), have previously been characterized, and several mutations in the band 3 gene have been found: amino acid substitutions at conserved positions in the membrane domain, nonsense and frameshift mutations. In HS patients bearing missense mutations, the mutated transcript was present, whereas only the normal transcript was found in HS patients with frameshift mutations. In the former group, the membrane expression deficiency of band 3 was significantly more important than that observed in the latter group of HS patients with frameshift mutations, suggesting that missense mutations may have a dominant negative effect. In the present study, transient and stable transfections of K562 and COS-7 cells were used to demonstrate, by immunoblots of cell lysates and immunofluorescence studies, that the band 3 membrane domain bearing the R490C mutation (band 3Bicetrel) is not targeted to the plasma membrane and is retained in the endoplasmic reticulum. Transient cotransfections of K562 cells with plasmid coding for the normal membrane domain of band 3, together with increasing amounts of plasmid coding for the mutated R490C membrane domain, demonstrated that the band 3 mutant polypeptide exerts a dominant negative effect on the plasma membrane targeting of the normal band 3.
Animals↗
[Molecular markers of clonality].
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Animals↗
[Polymorphism of aldose reductase gene and susceptibility to retinopathy and nephropathy in Caucasians with type 1 diabetes].
Polymorphisms of the -106 mutation and z - 2 or z + 2 microsatellites (-2.1 kb) of the Aldose Reductase (AR) gene have been associated to microangiopathic complications of the diabetes mellitus. The study aimed to establish a relation between the occurrence and progression of the renal and retinal complications and these polymorphisms. The genotypes were realised in 3 populations: DESIR (n = 369), non-diabetic control subjects from the general French population: GENEDIAB (n = 494), type 1 diabetic patients who are suffering from proliferative retinopathy associated with a variable seriousness nephropathy (absent: n = 157; incipient: n = 104; established: n = 126; advanced: n = 107); SURGENE (n = 310), type 1 diabetic patients whom the renal status is prospectively assessed since 1989 in one single center Angers University Hospital. The genotype of the -106 polymorphism was determined using the Molecular Beacons. For the microsatellites analysis, we used an automatized method (GeneScan Abi Prism 3100). There was a strong linkage disequilibrium between the z - 2 allele and the T allele (chi 2 = 120; p = 0.001). The frequency of the C-106T is similar for the DESIR and GENEDIAB cohorts (chi 2 = 3.32; p = 0.19); the Hardy Weinberg law was verified in this group (chi 2 = 0.001, 0.9; p = 1.5 and 0.5 respectively). The law was not verified for the SURGENE cohort (chi 2 = 4.7; p = 0.03) where the frequency of the TT genotype was significantly more important compared to the DESIR population (chi 2 = 6.4; p = 0.01). The z, z - 2 and z + 2 alleles was more frequent compared with other alleles (n = 909, 830 and 349; 39, 38 and 15%). The frequency of the C-106T and microsatellites genotypes did not parallel the nephropathy staging in the GENEDIAB population (chi 2 = 10.9, 2.7, 2.4; p = NS respectively). In the SURGENE population, the survival without renal events did not differ according C-106T and z - 2 or z + 2 microsatellites genotypes (log-rank: 0.6, 3.9, 0.1; p = NS respectively). At the end of the follow-up, we found an effect of the -106 mutation and of the z - 2 microsatellite on the staging of the retinopathy (chi 2 tendency test = 4.61, 0.12; p = 0.031, 0.02; 6 d.f., respectively). The logistic regression multivariable analysis shows that the retinopathy during the final evaluation is independently explained by several factors: diabetes duration (p < 0.0001; OR 21.756; 95% CI: 7.024-67.389), presence of nephropathy (p < 0.0001; OR: 4.086; 95% CI: 2.094-7.973), and genotype TT (p = 0.011; OR: 0.38; 95% CI: 0.18-0.803). In contrast, age of diabetes onset (p = 0.112; OR: 1.556; 95% CI: 0.9-2.692), median HbA1c (p = 0.164; OR: 1.479; 95% CI: 0.85-2.576) and sex (p = 0.156; OR: 1.495; 95% CI: 0.856-2.612) have no independent effect. In conclusion, the association of these AR genetic variants seems absent about the renal risk and slight about the retinal risk associated to the type 1 diabetes mellitus.
Adult↗