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. 2011 Apr;60(4):1349-53.
doi: 10.2337/db10-1008. Epub 2011 Mar 4.

Permanent Neonatal Diabetes and Enteric Anendocrinosis Associated With Biallelic Mutations in NEUROG3

Oscar Rubio-Cabezas  1 , Jan N Jensen, Maria I Hodgson, Ethel Codner, Sian Ellard, Palle Serup, Andrew T Hattersley
Affiliations

Permanent Neonatal Diabetes and Enteric Anendocrinosis Associated With Biallelic Mutations in NEUROG3

Oscar Rubio-Cabezas et al. Diabetes. 2011 Apr.

Abstract

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 malabsorptive diarrhea secondary to enteroendocrine cell dysgenesis VSports手机版. 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. V体育安卓版.

Results: Two different heterozygous point mutations in NEUROG3 were identified in the proband [c. 82G>T (p V体育ios版. 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 VSports最新版本. This finding confirms the essential role of NEUROG3 in islet development and function in humans. .

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Figures

FIG. 1.
FIG. 1.
A: Electropherograms and family pedigree showing inheritance of NEUROG3 mutations. Squares represent men, and circles represent women subjects. The black-filled symbol denotes the patient with neonatal diabetes, and the dot-filled symbols represent the unaffected heterozygous carriers. Genotype is shown underneath each symbol; N denotes the wild-type allele. B: Schematic organization of NEUROG3 protein. Numbers refer to the amino acids bordering the functional domains. The conservation across species of various residues within or nearby the bHLH domain is shown. (A high-quality color representation of this figure is available in the online issue.)
FIG. 2.
FIG. 2.
Endoscopically resected intestinal mucosa from the patient and a control subject. Enteroendocrine cells can normally be identified by staining the preparation for chromogranin A (left panels). No immunohistochemical reactivity was seen either in the duodenal or in the colonic tissue from the patient (right panels). (A high-quality digital representation of this figure is available in the online issue.)
FIG. 3.
FIG. 3.
A: Transactivation of the NEUROD1 promoter by wild-type (WT) and mutant NEUROG3 proteins in P19 cells. E28X activity is reduced to ∼25% compared with WT (P < 0.01 using a two-tailed Student t test), whereas L135P does not show activity over the vector control. Surprisingly, residual activity is seen when comparing E28X with the vector control (P < 0.00002). B: Whole-mount immunohistochemical detection of green fluorescent protein (GFP; green) and glucagon (red) in chicken embryos electroporated with WT and mutant NEUROG3 plasmids. WT NEUROG3 (B and B’), introduced into FoxA2 expressing endoderm of the prospective duodenum of 13–15 somite chicken embryos, induces the development of glucagon-expressing endocrine cells that delaminate from the duodenal epithelium, whereas control embryos (A and A’), or embryos expressing E28X (C and C’) and L135P (D and D’) mutants, do not develop such cells. A, B, C, and D show three-dimensional projections of the duodenum (duo) and dorsal pancreas (dp), whereas A’, B’, C’, and D’ show single optical sections from the same embryos. (A high-quality digital representation of this figure is available in the online issue.)
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References

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