Biallelic PDX1 (insulin promoter factor 1) mutations causing neonatal diabetes without exocrine pancreatic insufficiency

This is the final version. Available on open access from Wiley via the DOI in this recordAims: Recessive PDX1 (IPF1) mutations are a rare cause of pancreatic agenesis, with three cases reported worldwide. A recent report described two cousins with a homozygous hypomorphic PDX1 mutation causing permanent neonatal diabetes with subclinical exocrine insufficiency. The aim of our study was to investigate the possibility of hypomorphic PDX1 mutations in a large cohort of patients with permanent neonatal diabetes and no reported pancreatic hypoplasia or exocrine insufficiency. Methods: PDX1 was sequenced in 103 probands with isolated permanent neonatal diabetes in whom ABCC8, KCNJ11 and INS mutations had been excluded. Results: Sequencing analysis identified biallelic PDX1 mutations in three of the 103 probands with permanent neonatal diabetes (2.9%). One proband and his affected brother were compound heterozygotes for a frameshift and a novel missense mutation (p.A34fsX191; c.98dupC and p.P87L; c.260C>T). The other two probands were homozygous for novel PDX1 missense mutations (p.A152G; c.455C>G and p.R176Q; c.527G>A). Both mutations affect highly conserved residues located within the homeobox domain. None of the four cases showed any evidence of exocrine pancreatic insufficiency, either clinically, or, where data were available, biochemically. In addition a heterozygous nonsense mutation (p.C18X; c.54C>A) was identified in a fourth case. Conclusions: This study demonstrates that recessive PDX1 mutations are a rare but important cause of isolated permanent neonatal diabetes in patients without pancreatic hypoplasia/agenesis. Inclusion of the PDX1 gene in mutation screening for permanent neonatal diabetes is recommended as a genetic diagnosis reveals the mode of inheritance, allows accurate estimation of recurrence risks and confirms the requirement for insulin treatment. © 2013 The Authors. Diabetic Medicine © 2013 Diabetes UK.Diabetes UKEuropean Union FP

Type 2 Diabetes Risk Alleles Are Associated With Reduced Size at Birth

OBJECTIVE: Low birth weight is associated with an increased risk of type 2 diabetes. The mechanisms underlying this association are unknown and may represent intrauterine programming or two phenotypes of one genotype. The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion or action may predispose to type 2 diabetes and also reduce birth weight, since insulin is a key fetal growth factor. We tested whether common genetic variants that predispose to type 2 diabetes also reduce birth weight. RESEARCH DESIGN AND METHODS: We genotyped single-nucleotide polymorphisms (SNPs) at five recently identified type 2 diabetes loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2, and SLC30A8) in 7,986 mothers and 19,200 offspring from four studies of white Europeans. We tested the association between maternal or fetal genotype at each locus and birth weight of the offspring. RESULTS: We found that type 2 diabetes risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus (21 g [95% CI 11-31], P = 2 x 10(-5), and 14 g [4-23], P = 0.004, lower birth weight per risk allele, respectively). The 4% of offspring carrying four risk alleles at these two loci were 80 g (95% CI 39-120) lighter at birth than the 8% carrying none (P(trend) = 5 x 10(-7)). There were no associations between birth weight and fetal genotypes at the three other loci or maternal genotypes at any locus. CONCLUSIONS: Our results are in keeping with the fetal insulin hypothesis and provide robust evidence that common disease-associated variants can alter size at birth directly through the fetal genotype

Challenging Perceptions of Disability through Performance Poetry Methods: The "Seen but Seldom Heard" Project.

This paper considers performance poetry as a method to explore lived experiences of disability. We discuss how poetic inquiry used within a participatory arts-based research framework can enable young people to collectively question society’s attitudes and actions towards disability. Poetry will be considered as a means to develop a more accessible and effective arena in which young people with direct experience of disability can be empowered to develop new skills that enable them to tell their own stories. Discussion of how this can challenge audiences to critically reflect upon their own perceptions of disability will also be developed

Ion acceleration from microstructured targets irradiated by high-intensity picosecond laser pulses

Structures on the front surface of thin foil targets for laser-driven ion acceleration have been proposed to increase the ion source maximum energy and conversion efficiency. While structures have been shown to significantly boost the proton acceleration from pulses of moderate-energy fluence, their performance on tightly focused and high-energy lasers remains unclear. Here, we report the results of laser-driven three-dimensional (3D)-printed microtube targets, focusing on their efficacy for ion acceleration. Using the high-contrast (∼1012) PHELIX laser (150J, 1021W/cm2), we studied the acceleration of ions from 1-μm-thick foils covered with micropillars or microtubes, which we compared with flat foils. The front-surface structures significantly increased the conversion efficiency from laser to light ions, with up to a factor of 5 higher proton number with respect to a flat target, albeit without an increase of the cutoff energy. An optimum diameter was found for the microtube targets. Our findings are supported by a systematic particle-in-cell modeling investigation of ion acceleration using 2D simulations with various structure dimensions. Simulations reproduce the experimental data with good agreement, including the observation of the optimum tube diameter, and reveal that the laser is shuttered by the plasma filling the tubes, explaining why the ion cutoff energy was not increased in this regime.Fil: Bailly Grandvaux, M.. University of California at San Diego; Estados UnidosFil: Kawahito, D.. University of California at San Diego; Estados UnidosFil: McGuffey, C.. University of California at San Diego; Estados UnidosFil: Strehlow, J.. University of California at San Diego; Estados UnidosFil: Edghill, B.. University of California at San Diego; Estados UnidosFil: Wei, M.S.. Laboratory For Laser Energetics; Estados UnidosFil: Alexander, N.. General Atomics; Estados UnidosFil: Haid, A.. General Atomics; Estados UnidosFil: Brabetz, C.. Helmholtzzentrum Für Schwerionenforschung; AlemaniaFil: Bagnoud, V.. Helmholtzzentrum Für Schwerionenforschung; AlemaniaFil: Hollinger, R.. State University of Colorado - Fort Collins; Estados UnidosFil: Capeluto, Maria Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Rocca, J.J.. State University of Colorado - Fort Collins; Estados UnidosFil: Beg, F.N.. University of California at San Diego; Estados Unido

Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis

Heterozygous coding mutations in the INS gene that encodes preproinsulin were recently shown to be an important cause of permanent neonatal diabetes. These dominantly acting mutations prevent normal folding of proinsulin, which leads to beta-cell death through endoplasmic reticulum stress and apoptosis. We now report 10 different recessive INS mutations in 15 probands with neonatal diabetes. Functional studies showed that recessive mutations resulted in diabetes because of decreased insulin biosynthesis through distinct mechanisms, including gene deletion, lack of the translation initiation signal, and altered mRNA stability because of the disruption of a polyadenylation signal. A subset of recessive mutations caused abnormal INS transcription, including the deletion of the C1 and E1 cis regulatory elements, or three different single base-pair substitutions in a CC dinucleotide sequence located between E1 and A1 elements. In keeping with an earlier and more severe beta-cell defect, patients with recessive INS mutations had a lower birth weight (-3.2 SD score vs. -2.0 SD score) and were diagnosed earlier (median 1 week vs. 10 weeks) compared to those with dominant INS mutations. Mutations in the insulin gene can therefore result in neonatal diabetes as a result of two contrasting pathogenic mechanisms. Moreover, the recessively inherited mutations provide a genetic demonstration of the essential role of multiple sequence elements that regulate the biosynthesis of insulin in man

Referral rates for diagnostic testing support an incidence of permanent neonatal diabetes in three European countries of at least 1 in 260,000 live births

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Permanent Neonatal Diabetes Caused by Creation of an Ectopic Splice Site within the INS Gene

PublishedCase ReportsJournal ArticleResearch Support, Non-U.S. Gov'tBACKGROUND: The aim of this study was to characterize the genetic etiology in a patient who presented with permanent neonatal diabetes at 2 months of age. METHODOLOGY/PRINCIPAL FINDINGS: Regulatory elements and coding exons 2 and 3 of the INS gene were amplified and sequenced from genomic and complementary DNA samples. A novel heterozygous INS mutation within the terminal intron of the gene was identified in the proband and her affected father. This mutation introduces an ectopic splice site leading to the insertion of 29 nucleotides from the intronic sequence into the mature mRNA, which results in a longer and abnormal transcript. CONCLUSIONS/SIGNIFICANCE: This study highlights the importance of routinely sequencing the exon-intron boundaries and the need to carry out additional studies to confirm the pathogenicity of any identified intronic genetic variants.Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas (CIBERDEM)Instituto de Salud Carlos III of the Spanish Ministry of HealthFIS-programsWellcome Trus