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  • 1
    Online Resource
    Online Resource
    Homozygous Mutations in NEUROD1 Are Responsible for a Novel Syndrome of Permanent Neonatal Diabetes and Neurological Abnormalities
    American Diabetes Association ; 2010
    In:  Diabetes Vol. 59, No. 9 ( 2010-09-01), p. 2326-2331
    Details
    In: Diabetes, American Diabetes Association, Vol. 59, No. 9 ( 2010-09-01), p. 2326-2331
    Abstract: NEUROD1 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 METHODS We sequenced the NEUROD1 gene in 44 unrelated patients with permanent neonatal diabetes of unknown genetic etiology. RESULTS Two 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. CONCLUSIONS We 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.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db10-0011
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2010
    detail.hit.zdb_id: 1501252-9
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  • 2
    Online Resource
    Online Resource
    Association Studies of Genetic Variation in the WFS1 Gene and Type 2 Diabetes in U.K. Populations
    American Diabetes Association ; 2002
    In:  Diabetes Vol. 51, No. 4 ( 2002-04-01), p. 1287-1290
    Details
    In: Diabetes, American Diabetes Association, Vol. 51, No. 4 ( 2002-04-01), p. 1287-1290
    Abstract: Mutations in the WFS1 gene cause β-cell death, resulting in a monogenic form of diabetes known as Wolfram syndrome. The role of variation in WFS1 in type 2 diabetes susceptibility is not known. We sequenced the WFS1 gene in 29 type 2 diabetic probands and identified 12 coding variants. We used 152 parent-offspring trios to look for familial association; the R allele at residue 456 (P = 0.04) and the H allele at residue 611 (P = 0.05) as well as the R456-H611 haplotype (P = 0.032) were overtransmitted to affected offspring from heterozygous parents. In a further cohort of 327 type 2 diabetic subjects and 357 normoglycemic control subjects, the H611 allele and the R456-H611 haplotype were present in more type 2 diabetic subjects than control subjects (one-tailed P = 0.06 and P = 0.023, respectively). In a combined analysis, the H611 allele was present in 60% of all diabetes chromosomes and 55% of all control chromosomes (odds ratio [OR] 1.24 [95% CI 1.03–1.48] , P = 0.02), and the R456-H611 haplotype was significantly more frequent in type 2 diabetic subjects than in control subjects (60 vs. 54%, OR 1.29 [95% CI 1.08–1.54] , P = 0.0053). Our results provide the first evidence that variation in the WFS1 gene may influence susceptibility to type 2 diabetes.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/diabetes.51.4.1287
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2002
    detail.hit.zdb_id: 1501252-9
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  • 3
    Online Resource
    Online Resource
    Clinical Heterogeneity in Patients With FOXP3 Mutations Presenting With Permanent Neonatal Diabetes
    American Diabetes Association ; 2009
    In:  Diabetes Care Vol. 32, No. 1 ( 2009-01-01), p. 111-116
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 32, No. 1 ( 2009-01-01), p. 111-116
    Abstract: 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 = 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 = 2) or nephrotic syndrome (n = 1) and survival to 12–15 years. CONCLUSIONS—FOXP3 mutations result in ∼4% 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.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc08-1188
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2009
    detail.hit.zdb_id: 1490520-6
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  • 4
    Online Resource
    Online Resource
    Pharmacological characterisation of a cell line expressing GABAB1b and GABAB2 receptor subunits
    Elsevier BV ; 2003
    In:  Biochemical Pharmacology Vol. 65, No. 7 ( 2003-04), p. 1103-1113
    Details
    In: Biochemical Pharmacology, Elsevier BV, Vol. 65, No. 7 ( 2003-04), p. 1103-1113
    Type of Medium: Online Resource
    ISSN: 0006-2952
    URL: Article
    DOI: 10.1016/S0006-2952(02)01658-1
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2003
    detail.hit.zdb_id: 1496199-4
    SSG: 15,3
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