Permanent Neonatal Diabetes and Enteric Anendocrinosis Associated With Biallelic Mutations in NEUROG3.
Permanent Neonatal Diabetes and Enteric Anendocrinosis Associated With Biallelic Mutations in NEUROG3.
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DOI：
10.2337/db10-1008
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发表时间：
2011-04
期刊：
影响因子：
7.7
通讯作者：
Hattersley AT
中科院分区：
文献类型：
--
作者：
Rubio-Cabezas O;Jensen JN;Hodgson MI;Codner E;Ellard S;Serup P;Hattersley AT
NEUROG3在胰岛和肠内分泌细胞的发育中起核心作用。最近，NEUROG3的纯合子次胚错义突变与一种罕见的先天性吸收不良腹泻继发于肠内分泌细胞发育不良有关。有趣的是，这些患者没有患上新生儿糖尿病，而是患上了儿童期糖尿病。我们假设NEUROG3的零突变可能是导致永久性新生儿糖尿病和严重先天性吸收不良腹泻患者疾病的原因。从基因组DNA中扩增并测序了NEUROG3的单编码外显子。通过测定其在体外与NEUROD1启动子中的E-box元件结合的能力，以及在蛋鸡内胚层电穿孔后诱导异位内分泌细胞形成和细胞分层的能力，对突变蛋白亚型进行了功能表征。在先证者中鉴定出两种不同的NEUROG3杂合点突变[c]。82G>T （p.E28X）和C . 404t >c (p.L135P)]，每个都从未受影响的亲本遗传。体外和体内功能研究表明，突变异构体具有生物活性。与此一致的是，在患者的肠道活检样本中未检测到肠内分泌细胞。神经原素3的严重缺乏导致一种罕见的新型永久性新生儿糖尿病。这一发现证实了NEUROG3在人类胰岛发育和功能中的重要作用。
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. 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. 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. 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. 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.
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