WRS is the most common cause of permanent neonatal diabetes mellitus in consanguineous pedigrees. In addition to testing patients with a definite clinical diagnosis, EIF2AK3 should be tested in patients with isolated neonatal diabetes diagnosed after 3 wk of age from known consanguineous families, isolated populations, or countries in which inbreeding is frequent.
Recent data suggest that common variation in the transcription factor 7-like 2 (TCF7L2) gene is associated with type 2 diabetes. Evaluation of such associations in independent samples provides necessary replication and a robust assessment of effect size. Using four TCF7L2 single nucleotide polymorphisms (SNPs; including the two most associated in the previous study), we conducted a casecontrol study in 2,158 type 2 diabetic subjects and 2,574 control subjects and a family-based association analysis in 388 parent-offspring trios all from the U.K. All SNPs showed powerful associations with diabetes in the casecontrol analysis, with strongest effects at rs7903146 (allele-wise relative risk 1.36 [95% CI 1.24 -1.48], P ؍ 1.3 ؋ 10 ؊11 ). Data were consistent with a multiplicative model. The family-based analyses provided independent evidence for association at all loci (e.g., rs4506565, 62% transmission, P ؍ 7 ؋ 10 ؊5 ) with no parent-of-origin effects. The frequency of diabetes-associated TCF7L2 genotypes was greater in cases ascertained for positive family history and early onset (rs4606565, P ؍ 0.02); the population-attributable risk, estimated from the least-selected cases, is ϳ16%. The overall evidence for association for these variants (P ؍ 4.4 ؋ 10 ؊14 combining case-control and family-based analyses for rs4506565) exceeds genome-wide significance criteria and clearly establishes TCF7L2 as a type 2 diabetes susceptibility gene of substantial importance. Diabetes
HNF-1beta mutations are a rare cause of neonatal diabetes as well as pancreatic exocrine and endocrine dysfunction. Low birth weight is a common feature of patients with HNF-1beta mutations and is consistent with reduced insulin secretion in utero. These findings support a key role for HNF-1beta in early pancreatic progenitor cells in man.
OBJECTIVE -Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is caused by FOXP3 mutations. We aimed to determine the prevalence, genetics, and clinical phenotype of FOXP3 mutations in a large cohort with permanent neonatal diabetes (PNDM).RESEARCH DESIGN AND METHODS -The 11 coding exons and the polyadenylation region of FOXP3 were sequenced in 26 male subjects with diabetes diagnosed before 6 months of age in whom common genetic causes of PNDM had been excluded. Ten subjects had at least one additional immune-related disorder, and the remaining 16 had isolated diabetes.RESULTS -We identified four hemizygous FOXP3 mutations in 6 of 10 patients with associated immune-related disorders and in 0 of 16 patients with isolated diabetes (P ϭ 0.002). Three patients with two novel mutations (R337Q and P339A) and the previously reported L76QfsX53 developed classic IPEX syndrome and died within the first 13 months. The novel mutation V408M was found in three patients from two unrelated families and had a mild phenotype with hypothyroidism and autoimmune enteropathy (n ϭ 2) or nephrotic syndrome (n ϭ 1) and survival to 12-15 years.CONCLUSIONS -FOXP3 mutations result in ϳ4% of cases of male patients with permanent diabetes diagnosed before 6 months. Patients not only have classic IPEX syndrome but, unexpectedly, may have a more benign phenotype. FOXP3 sequencing should be performed in any male patient with the diagnosis of diabetes in the first 6 months who develops other possible autoimmune-associated conditions, even in the absence of full IPEX syndrome.
OBJECTIVENEUROD1 is expressed in both developing and mature β-cells. Studies in mice suggest that this basic helix-loop-helix transcription factor is critical in the development of endocrine cell lineage. Heterozygous mutations have previously been identified as a rare cause of maturity-onset diabetes of the young (MODY). We aimed to explore the potential contribution of NEUROD1 mutations in patients with permanent neonatal diabetes.RESEARCH DESIGN AND METHODSWe sequenced the NEUROD1 gene in 44 unrelated patients with permanent neonatal diabetes of unknown genetic etiology.RESULTSTwo homozygous mutations in NEUROD1 (c.427_ 428del and c.364dupG) were identified in two patients. Both mutations introduced a frameshift that would be predicted to generate a truncated protein completely lacking the activating domain. Both patients had permanent diabetes diagnosed in the first 2 months of life with no evidence of exocrine pancreatic dysfunction and a morphologically normal pancreas on abdominal imaging. In addition to diabetes, they had learning difficulties, severe cerebellar hypoplasia, profound sensorineural deafness, and visual impairment due to severe myopia and retinal dystrophy.CONCLUSIONSWe describe a novel clinical syndrome that results from homozygous loss of function mutations in NEUROD1. It is characterized by permanent neonatal diabetes and a consistent pattern of neurological abnormalities including cerebellar hypoplasia, learning difficulties, sensorineural deafness, and visual impairment. This syndrome highlights the critical role of NEUROD1 in both the development of the endocrine pancreas and the central nervous system in humans.
Wolfram syndrome, an autosomal recessive disorder characterized by diabetes mellitus and optic atrophy, is caused by mutations in the WFS1 gene encoding an endoplasmic reticulum (ER) membrane protein, Wolframin. Although its precise functions are unknown, Wolframin deficiency increases ER stress, impairs cell cycle progression and affects calcium homeostasis. To gain further insight into its function and identify molecular partners, we used the WFS1-C-terminal domain as bait in a yeast two-hybrid screen with a human brain cDNA library. Na+/K+ ATPase beta1 subunit was identified as an interacting clone. We mapped the interaction to the WFS1 C-terminal and transmembrane domains, but not the N-terminal domain. Our mapping data suggest that the interaction most likely occurs in the ER. We confirmed the interaction by co-immunoprecipitation in mammalian cells and with endogenous proteins in JEG3 placental cells, neuroblastoma SKNAS and pancreatic MIN6 beta cells. Na+/K+ ATPase beta1 subunit expression was reduced in plasma membrane fractions of human WFS1 mutant fibroblasts and WFS1 knockdown MIN6 pancreatic beta-cells compared with wild-type cells; Na+/K+ ATPase alpha1 subunit expression was also reduced in WFS-depleted MIN6 beta cells. Induction of ER stress in wild-type cells only partly accounted for the reduced Na+/K+ ATPase beta1 subunit expression observed. We conclude that the interaction may be important for Na+/K+ ATPase beta1 subunit maturation; loss of this interaction may contribute to the pathology seen in Wolfram syndrome via reductions in sodium pump alpha1 and beta1 subunit expression in pancreatic beta-cells.
SB‐258585 (4‐Iodo‐N‐[4‐methoxy‐3‐(4‐methyl‐piperazin‐1‐yl)‐phenyl]‐benzenesulphonamide) is a high affinity ligand at 5‐HT6 receptors. It displays over 100 fold selectivity for the 5‐HT6 receptor over all other 5‐HT receptors tested so far. SB‐258585 has been radiolabelled, to high specific activity, for its characterization as a 5‐HT6 receptor selective radioligand.
[125I]‐SB‐258585 bound, with high affinity, to a single population of receptors in a cell line expressing human recombinant 5‐HT6 receptors. Kinetic and saturation binding experiments gave pKD values of 9.01±0.09 and 9.09±0.02, respectively.
In membranes derived from rat or pig striatum and human caudate putamen, [125I]‐SB‐258585 labelled a single site with high levels (>60%) of specific binding. Saturation analysis revealed pKD values of 8.56±0.07 for rat, 8.60±0.10 for pig and 8.90±0.02 for human. Bmax values for the tissues ranged from 173±23 and 181±25 fmol mg−1 protein in rat and pig striatum, respectively, to 215±41 fmol mg−1 protein in human caudate putamen.
The pKi rank order of potency for a number of compounds, determined in competition binding assays with [125I]‐SB‐258585, at human caudate putamen membranes was: SB‐271046>SB‐258585>SB‐214111>methiothepin>clozapine>5‐Me‐OT>5‐HT>Ro 04‐6790>mianserin>ritanserin=amitriptyline>5‐CT>mesulergine. Similar profiles were obtained from pig and rat striatal membranes and recombinant 5‐HT6 receptors; data from the latter correlated well with [3H]‐LSD binding.
Thus, [125I]‐SB‐258585 is a high affinity, selective radioligand which can be used to label both recombinant and native 5‐HT6 receptors and will facilitate further characterization of this receptor subtype in animal and human tissues.
British Journal of Pharmacology (2000) 130, 1597–1605; doi:
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