28 research outputs found
Classification of and risk factors for hematologic complications in a French national cohort of 102 patients with Shwachman-Diamond syndrome.
International audienceBACKGROUND: Patients with the Shwachman-Diamond syndrome often develop hematologic complications. No risk factors for these complications have so far been identified. The aim of this study was to classify the hematologic complications occurring in patients with Shwachman-Diamond syndrome and to investigate the risk factors for these complications. DESIGN AND METHODS: One hundred and two patients with Shwachman-Diamond syndrome, with a median follow-up of 11.6 years, were studied. Major hematologic complications were considered in the case of definitive severe cytopenia (i.e. anemia <7 g/dL or thrombocytopenia <20 × 10(9)/L), classified as malignant (myelodysplasia/leukemia) according to the 2008 World Health Organization classification or as non-malignant. RESULTS: Severe cytopenia was observed in 21 patients and classified as malignant severe cytopenia (n=9), non-malignant severe cytopenia (n=9) and malignant severe cytopenia preceded by non-malignant severe cytopenia (n=3). The 20-year cumulative risk of severe cytopenia was 24.3% (95% confidence interval: 15.3%-38.5%). Young age at first symptoms (<3 months) and low hematologic parameters both at diagnosis of the disease and during the follow-up were associated with severe hematologic complications (P<0.001). Fifteen novel SBDS mutations were identified. Genotype analysis showed no discernible prognostic value. CONCLUSIONS Patients with Shwachman-Diamond syndrome with very early symptoms or cytopenia at diagnosis (even mild anemia or thrombocytopenia) should be considered at a high risk of severe hematologic complications, malignant or non-malignant. Transient severe cytopenia or an indolent cytogenetic clone had no deleterious value
New evidence of a mitochondrial genetic background paradox: Impact of the J haplogroup on the A3243G mutation
International audienceBackground: The A3243G mutation in the tRNALeu gene (UUR), is one of the most common pathogenic mitochondrial DNA (mtDNA) mutations in France, and is associated with highly variable and heterogeneous disease phenotypes. To define the relationships between the A3243G mutation and mtDNA backgrounds, we determined the haplogroup affiliation of 142 unrelated French patients – diagnosed as carriers of the A3243G mutation – by control-region sequencing and RFLP survey of their mtDNAs. Results: The analysis revealed 111 different haplotypes encompassing all European haplogroups, indicating that the 3243 site might be a mutational hot spot. However, contrary to previous findings, we observed a statistically significant underepresentation of the A3243G mutation on haplogroup J in patients (p = 0.01, OR = 0.26, C.I. 95%: 0.08–0.83), suggesting that might be due to a strong negative selection at the embryo or germ line stages. Conclusion: Thus, our study supports the existence of mutational hotspot on mtDNA and a "haplogroup J paradox," a haplogroup that may increase the expression of mtDNA pathogenic mutations, but also be beneficial in certain environmental contexts
Pregnancy in Women With Monogenic Diabetes due to Pathogenic Variants of the Glucokinase Gene: Lessons and Challenges
International audienceHeterozygous loss-of-function variants of the glucokinase (GCK) gene are responsible for a subtype of maturity-onset diabetes of the young (MODY). GCK-MODY is characterized by a mild hyperglycemia, mainly due to a higher blood glucose threshold for insulin secretion, and an up-regulated glucose counterregulation. GCK-MODY patients are asymptomatic, are not exposed to diabetes long-term complications, and do not require treatment. The diagnosis of GCK-MODY is made on the discovery of hyperglycemia by systematic screening, or by family screening. The situation is peculiar in GCK-MODY women during pregnancy for three reasons: 1. the degree of maternal hyperglycemia is sufficient to induce pregnancy adverse outcomes, as in pregestational or gestational diabetes; 2. the probability that a fetus inherits the maternal mutation is 50% and; 3. fetal insulin secretion is a major stimulus of fetal growth. Consequently, when the fetus has not inherited the maternal mutation, maternal hyperglycemia will trigger increased fetal insulin secretion and growth, with a high risk of macrosomia. By contrast, when the fetus has inherited the maternal mutation, its insulin secretion is set at the same threshold as the mother’s, and no fetal growth excess will occur. Thus, treatment of maternal hyperglycemia is necessary only in the former situation, and will lead to a risk of fetal growth restriction in the latter. It has been recommended that the management of diabetes in GCK-MODY pregnant women should be guided by assessment of fetal growth by serial ultrasounds, and institution of insulin therapy when the abdominal circumference is ≥ 75th percentile, considered as a surrogate for the fetal genotype. This strategy has not been validated in women with in GCK-MODY. Recently, the feasibility of non-invasive fetal genotyping has been demonstrated, that will improve the care of these women. Several challenges persist, including the identification of women with GCK-MODY before or early in pregnancy, and the modalities of insulin therapy. Yet, retrospective observational studies have shown that fetal genotype, not maternal treatment with insulin, is the main determinant of fetal growth and of the risk of macrosomia. Thus, further studies are needed to specify the management of GCK-MODY pregnant women during pregnancy
The Gly482Ser polymorphism in the peroxisome proliferator-activated receptor-gamma coactivator-1 gene is associated with hypertension in type 2 diabetic men
Aims/hypothesis. Peroxisome proliferator-activated receptor-gamma coactivator-1 (PPARGC1) acts as a cofactor for several nuclear hormone receptors in many tissues and organs implicated in blood pressure regulation. Here, we assessed the association between the Gly482Ser variant of PPARGC1 and the arterial hypertension frequently found in subjects with type 2 diabetes.Methods. We studied a group of 479 men and 253 women with type 2 diabetes. Arterial hypertension was present in 70% of the men and in 73% of the women. Genotypes were examined by PCR restriction fragment length polymorphism. A logistic regression analysis was performed to assess the covariables associated with arterial hypertension.Results. There was an association between Ser allele homozygosis and arterial hypertension in type 2 diabetic men (odds ratio of 2.52 vs Gly allele homozygosis; 95% CI: 1.32-5.00; p=0.0064), but not in women. the prevalence of arterial hypertension in type 2 diabetic men was 77% vs 73% vs 67% for Ser-Ser, Gly-Ser and Gly-Gly carriers respectively (p=0.021). Age, BMI, the use of insulin, and triglyceride and creatinine levels were also independently associated with arterial hypertension in this cohort.Conclusions/interpretation. We have observed a sex-specific association between the PPARGC-1 gene Gly482Ser polymorphism and arterial hypertension in type 2 diabetic men. Further studies are needed to investigate the genetic, biochemical and pathophysiological basis of this allelic association.Hop St Vincent de Paul, INSERM, Res Unit 561, F-75014 Paris, FranceUniversidade Federal de São Paulo, Mol Endocrinol Lab, São Paulo, BrazilCochin Hosp, Dept Immunol & Diabetol, Paris, FranceHop St Antoine, Mol Biol Unit, F-75571 Paris, FranceUniversidade Federal de São Paulo, Mol Endocrinol Lab, São Paulo, BrazilWeb of Scienc
The Knudson's two-hit phenomenon and timing of somatic mutation may account for the phenotypic diversity of focal congenital hyperinsulinism
Prevalence of maturity-onset diabetes of the young mutations in Brazilian families with autosomal-dominant early-onset type 2 diabetes
Universidade Federal de São Paulo, Dept Internal Med Endocrinol, São Paulo, BrazilINSERM U342, Paris, FranceFdn Jean Dausset, CEPH, Paris, FranceUniversidade Federal de São Paulo, Dept Internal Med Endocrinol, São Paulo, BrazilWeb of Scienc
Germline hepatocyte nuclear factor 1 alpha and 1 beta mutations in renal cell carcinomas
Mutations in one copy of the hepatocyte nuclear factors (HNF) 1alpha and 1beta homeodomain containing transcription factors predispose the carrier to maturity-onset diabetes of the young (MODY) types 3 and 5, respectively. Moreover, previous identification of biallelic inactivation of HNF1alpha in hepatocellular adenoma identified its tumor suppressor function in hepatocarcinogenesis. The seminal observation of an ovarian carcinoma in a MODY5 patient who subsequently developed a chromophobe renal cell carcinoma, prompted us to screen for HNF1beta and HNF1alpha inactivation in a series of 20 ovarian and 35 renal neoplasms. Biallelic HNF1beta inactivation was found in two of 12 chromophobe renal carcinomas by association of a germline mutation and a somatic gene deletion. In these cases, the expression of PKHD1 (polycystic kidney and hepatic disease 1) and UMOD (Uromodulin), two genes regulated by HNF1beta, was turned off. Interestingly, in two of 13 clear cell renal carcinomas, we found a monoallelic germline mutation of HNF1alpha with no associated suppression of target mRNA expression. In normal and tumor renal tissues, we showed the existence of a network of transcription factors differentially regulated in tumor subtypes. We identified two related clusters of co-regulated genes associating HNF1beta, PKHD1 and UMOD in the first group and HNF1alpha, HNF4alpha, FABP1 and UGT2B7 in the second group. Finally, these results suggest that germline mutations of HNF1beta and HNF1alpha may predispose to renal tumors. Furthermore, we suggest that HNF1beta functions as a tumor suppressor gene in chromophobe renal cell carcinogenesis through a PKHD1 expression control