Association of calpain-10 polymorphisms with type 2 diabetes in the Tunisian population.

BACKGROUND: Genome-wide analyses of the genetic predisposition to type 2 diabetes mellitus (T2DM) in different isolates and populations have identified regions of interest called non insulin-dependent diabetes mellitus (NIDDM) 1, 2, 3 and 4. At the NIDDM1 locus (2q37.3), calpain-10 (CAPN10) encodes for a ubiquitously expressed protease implicated in the two fundamental pathophysiological aspects of T2DM. This is a report of the results of a study of the association of four CAPN10 polymorphisms with T2DM in the Tunisian population. PARTICIPANTS AND METHODS: A total of 222 T2DM patients with a diabetes duration of 10 years or more and 206 healthy controls were enrolled to analyze the frequency distribution of four CAPN10 polymorphisms (UCSNP-43, UCSNP-19, UCSNP-110 and UCSNP-63) using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in the Tunisian population. We also investigated the association of T2DM with different haplotypes and haplotype combinations. RESULTS: Only the A allele of UCSNP-43 showed an association with T2DM (odds ratio, OR=1.86). We also identified a novel combination of haplotypes (121/221) defined by three polymorphisms (UCNSP-43, -19 and -63) that is associated with an increased risk of T2DM (OR=2.38). CONCLUSION: In this study involving the Tunisian population, we identified genetic variants within CAPN10 that are linked with T2DM and a novel haplotype combination, 121/221, associated with an increased susceptibility to T2DM.

Risk genotypes and haplotypes of the GLUT1 gene for type 2 diabetic nephropathy in the Tunisian population.

OBJECTIVE: Diabetic nephropathy (DN) is a long-term complication of both type 1 and type 2 diabetes. Genetic studies on DN have been of little help so far, since several genetic association studies have shown conflicting results. Here we report the findings of a case-control study on five SNPs in the glucose transporter 1 (GLUT1) gene. The study investigated the association of five GLUT1 genotypes and haplotypes with DN. RESEARCH DESIGN AND METHODS: All subjects, 126 DN (cases) and 273 type 2 diabetes (controls), were genotyped using the polymerase chain reaction restriction fragment length polymorphism. RESULTS: The TT and the AA genotypes of the Haell and Enh2 SNP1, increased the risk of DN. The study also identified CGT as the highest risk haplotype (4.4-fold) followed by CAT with an increased risk of DN of 2.6-fold. CONCLUSIONS: The GLUT1 gene confers susceptibility to DN in type 2 diabetes patients in the Tunisian population.

[Intraepithelial carcinoma and invasive carcinoma of the sclero-corneal limbus. Anatomo-clinical study apropos of 20 cases]. / Carcinome intraépithélial et carcinome invasif du limbe scléro-cornéen. Etude anatomo-clinique à propos de 20 cas.

We report a retrospective multicentric study of 20 cases of sclero-corneal limbus tumours carcinome including 9 cases of Bowen's disease and 11 squamous cell carcinomas. These cases were observed over two 10 and 20-year periods in two pathology departments. Epidemiological, clinical, pathological and therapeutic data as well as the clinical course were studied and the results compared with a large review of the literature. The mean age of the patients was 38 years for Bowen's disease and 47 for carcinoma. Two young subjects, 5 and 22 years, had xeroderma pigmentosum and had Bowen's disease and an epidermoid microinvasive carcinoma, respectively. All of the patients with Bowen's disease were men and were more than 90% of the patients with carcinoma. Tumour size was greater in carcinomas (7 to 10 mm) than in Bowen's disease (1 to 5 mm). All tumours were unilateral. Clinical manifestations included irritative or inflammatory reactions in one-fourth of the patients with Bowen's disease and in one-third of those with carcinoma. Pathology examination revealed an intact basal membrane separating healthy tissue from Bowen's lesions which showed disrupted cell architecture mostly involving the medial layers of the epithelium in 37% of the cases. All of the lesions were treated by exeresis. No recurrence has been observed after a follow-up of 1 month to 2 years for Bowen's disease and 1 year (maximum) for squamous cell carcinomas.

[Ag-NORS and non-pigmented tumors of the sclerocorneal limbus. Apropos of 20 cases]. / Ag-NORS et tumeurs non pigmentées du limbe scléro-cornéen. A propos de 20 cas.

We studied nucleolar organizers (Ag-NORS) in 20 cases of ocular limbic tumours of which 7 were Bowen disease or intraepithelial carcinoma and 13 were invasive carcinomas. The NOR-Index, reflecting cellular activity, increased from intraepithelial carcinoma (3.97) to microinvasive (5.45) and invasive carcinoma (5.81). Results of Nor-Index, reflecting proliferation, was in agreement with other technics such as immuno-labelling with Ki67 and PCNA antibodies.

[Ocular findings in Alport syndrome: 32 case studies]. / Atteinte oculaire au cours du syndrome d'Alport. A propos de 32 cas.

BACKGROUND: Alport syndrome is an inherited disease resulting in kidney failure, hearing loss, and ocular abnormalities. The purpose of this study was to describe the incidence and type of ocular abnormalities and to determine inheritance of this syndrome in our population. PATIENTS AND METHODS: A total of 32 patients, from ten different families in South Tunisia, underwent a complete ocular examination. Inheritance was determined using pedigrees and genotyping. RESULTS: The best corrected visual acuity was 7.6/10. Biomicroscopy showed polymorphous dystrophy in 3%, anterior lenticonus in 28%, lens opacities in 3%, cataract in 19%, and retinal flecks in 37%. The genetic survey found five families with X-linked Alport syndrome, four families with recessive autosomal disease, and one family with dominant autosomal disease. DISCUSSION: Ocular abnormalities have been reported in 9%-82% of Alport syndrome patients. They are rare in childhood and increase in frequency and severity with age. The types of ocular defects described mostly involve the lens, the retina and more rarely the cornea. The most common changes are anterior lenticonus and perimacular retinal flecks. In approximately 85%, Alport syndrome is X-linked. In the remaining 15%, the transmission is autosomal recessive and exceptionally autosomal dominant. CONCLUSION: Ocular examination is a precious help for Alport syndrome diagnosis. It can also determine the prognosis of nephropathy.

Association of glucose transporter 1 polymorphisms with type 2 diabetes in the Tunisian population.

BACKGROUND: T2DM is a complex metabolic disease. Genetic studies on T2DM have been of little help so far because several genetic association studies have shown conflicting results. In this study, we report the findings of a case-control study on three SNPs in the GLUT1 gene. For this, we investigated the association of GLUT1 genotypes and haplotypes with T2DM. RESEARCH DESIGN AND METHODS: All 273 T2DM subjects (cases) and 343 healthy subjects (controls) were genotyped using the polymerase chain reaction restriction fragment length polymorphism. RESULTS: Results showed that the GT genotype of XbaI SNP could increase the risk of susceptibility to T2DM to 2.4 and that TAT is a 'risk haplotype' conferring a risk of 3.4 to T2DM. CONCLUSION: The TAT haplotype of the GLUT1 gene confers susceptibility to T2DM in the Tunisian population.

Association and linkage studies of the 20q11.2 region (GRD-2 locus) with Graves' disease in the Tunisian population.

OBJECTIVE: A genome-wide screen has shown linkage to the GRD-2 locus in Graves' disease (GD). Furthermore, a positional candidate gene maps to this locus; the CD40 gene has been reported to be associated and may predispose to the disease. The aim of this study was to replicate/reject the GRD-2 and to determine if the single nucleotide polymorphism (SNP) of the CD40 (CD40 C/T-1) confers susceptibility to GD. METHODS: The present study examined a dataset of 11 families with GD using 10 microsatellite markers and a case-control study consisting of 76 sporadic GD patients and 66 healthy subjects to determine the implication of the GRD-2. Both non-parametric linkage and association tests were performed. Genotyping of the CD40 C/T-1 was carried out using a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). RESULTS: The intrafamilial association and the case-control study showed no association between CD40 C/T-1 and GD. In addition, a high percentage of the C allele (96.9%) of CD40 SNP among control data was observed. The linkage analyses showed that the highest non-parametric LOD score was 1.67 at the D20S119 marker and the maximum attainable LOD score was 1.66. This result provides interesting evidence for linkage between GRD-2 and GD. CONCLUSION: The CD40 gene seems to be not associated with GD in the Tunisian population, whereas the GRD-2 locus could harbour other candidate gene(s) to the genetic susceptibility of GD.

[Ocular manifestations associated with nephronophthisis and genetic study in three Tunisian families]. / Analyse des manifestations oculaires associées à la néphronophtise et étude génétique chez trois familles tunisiennes.

PURPOSE: Nephronophthisis is a familial interstitial nephropathy with an autosome recessive mode of transmission. In some cases, it is associated with ocular manifestations such as retinitis pigmentosa in Senior-Løken syndrome. We report ocular abnormalities and genetic results in three affected Tunisian families. PATIENTS AND METHODS: Twenty-two members of these three families underwent a complete ophthalmologic examination (visual acuity, slit lamp biomicroscopy, ophthalmoscopy, and retinal electrophysiology). For genetic study, all individuals were genotyped and underwent a genomic sequence. RESULTS: Twenty-two subjects, nine of whom presented nephronophthisis, were included in this study. Retinitis pigmentosa was found in three cases. Our genetic study demonstrated that patients belonging to family 1 had homozygous deletions in NPHP1, all affected individuals from family 3 were linked to NPHP4 and presented a deletion in exons 2 and 3. Results are pending for patients in family 2. CONCLUSION: Senior-Løken syndrome is a rare hereditary disease that combines familial juvenile nephronophthisis and retinitis pigmentosa. This association was described in the literature in 39%-43% of cases. In our study, it was approximately 33% of cases. The genetic study can sometimes obviate the need for renal puncture, especially when the homozygous deletion of NPHP1 gene is confirmed.

Autosomal dominant Alport's syndrome: study of a large Tunisian family.

Alport's syndrome is a hereditary nephritis that may lead to end-stage renal disease (ESRD) in early adult life. It is a clinically and genetically heterogeneous nephropathy. Alport's syndrome is often associated with sensorineural deafness and/or ocular abnormalities. In contrast with the well-known X-linked phenotype, very little is known about the autosomal dominant form caused by mutations in COL4A3 and COL4A4 in the chromosome region 2q35-q37. We describe a Tunisian family with autosomal dominant Alport's syndrome in which males and females were equally affected. Two members reached ESRD at age 40 and 53 years, respectively. Three members experienced isolated microhematuria and one member experienced sensorineural deafness. No eye abnormalities were observed. Immunohistochemical studies showed a normal distribution of the alpha5 (type IV collagen) chain in the epidermal basement membrane. Genetic analysis demonstrated that a common haplotype co-segregated with the disease in the heterozygous state in all affected patients, thereby, confirming an autosomal dominant mode of inheritance. The same haplotype was observed in two asymptomatic children. We conclude that autosomal dominant Alport's syndrome, follows a rare mode of inheritance and exhibits a milder phenotype than usually observed in classic X-linked Alport's syndrome. The frequency of this mode of inheritance should be confirmed by a larger study.