Homozygous mutations in NEUROD1 are responsible for a novel syndrome of permanent neonatal diabetes and neurological abnormalities.
Homozygous mutations in NEUROD1 are responsible for a novel syndrome of permanent neonatal diabetes and neurological abnormalities.
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DOI：
10.2337/db10-0011
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发表时间：
2010-09
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;Minton JA;Kantor I;Williams D;Ellard S;Hattersley AT
NEUROD1在发育和成熟的β细胞中均有表达。小鼠的研究表明，这种基本的螺旋-环-螺旋转录因子在内分泌细胞谱系的发育中起着至关重要的作用。杂合突变以前被确定为年轻人成熟型糖尿病（MODY）的罕见原因。我们的目的是探讨NEUROD1突变在新生儿永久性糖尿病患者中的潜在作用。我们对44例遗传病因不明的无血缘关系的永久性新生儿糖尿病患者的NEUROD1基因进行了测序。在两例患者中发现了两个纯合突变（c. 427_428del和c.364dupG）。这两个突变都引入了一个移码，预计会产生一个完全缺乏激活域的截断蛋白。两例患者均在出生后2个月内被诊断为永久性糖尿病，没有外分泌胰腺功能障碍的证据，腹部影像学显示胰腺形态正常。除糖尿病外，他们还有学习困难、严重小脑发育不全、深度感音神经性耳聋以及严重近视和视网膜营养不良导致的视力障碍。我们描述了一种新的临床综合征，由纯合子丧失功能突变的结果在NEUROD1。其特征是永久性新生儿糖尿病和一贯的神经异常模式，包括小脑发育不全、学习困难、感音神经性耳聋和视力障碍。该综合征强调了NEUROD1在人类内分泌胰腺和中枢神经系统发育中的关键作用。
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. We sequenced the NEUROD1 gene in 44 unrelated patients with permanent neonatal diabetes of unknown genetic etiology. 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. 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.