期刊
DIABETES
卷 60, 期 4, 页码 1349-1353出版社
AMER DIABETES ASSOC
DOI: 10.2337/db10-1008
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资金
- European Union [LSHM-CT-2006-518153]
- Wellcome Trust [067463/Z/2/Z, 083270/Z/07/Z]
- Instituto de Salud Carlos III [FIS CM06/00013]
- Juvenile Diabetes Research Foundation [10-2008-580]
- National Institute for Health Research funded Peninsula Clinical Research Facility
- Wellcome Trust [083270/Z/07/Z] Funding Source: Wellcome Trust
OBJECTIVE-NEUROG3 plays a central role in the development of both pancreatic islets and enteroendocrine cells. Homozygous hypomorphic missense mutations in NEUROG3 have been recently associated with a rare form of congenital malabsolptive diarrhea secondary to enteroendocrine cell dysgenesis. Interestingly, the patients did not develop neonatal diabetes but childhood-onset diabetes. We hypothesized that null mutations in NEUROG3 might be responsible for the disease in a patient with permanent neonatal diabetes and severe congenital malabsorptive diarrhea. RESEARCH DESIGN AND METHODS The single coding exon of NEUROG3 was amplified and sequenced from genomic DNA. The mutant protein isoforms were functionally characterized by measuring their ability to bind to an E-box element in the NEUROD1 promoter in vitro and to induce ectopic endocrine cell formation and cell delamination after in ovo chicken endoderm electroporation. RESULTS Two different heterozygous point mutations in NEUROG3 were identified in the proband [c.82G > T (p.E28X) and c.404T > C (p.L135P)], each being inherited from an unaffected parent. Both in vitro and in vivo functional studies indicated that the mutant isoforms are biologically inactive. In keeping with this, no enteroendocrine cells were detected in intestinal biopsy samples from the patient. CONCLUSIONS Severe deficiency of neurogenin 3 causes a rare novel subtype of permanent neonatal diabetes. This finding confirms the essential role of NEUROG3 in islet development and function in humans. Diabetes 60:1349-1353, 2011
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