A novel hypomorphic PDX1 mutation responsible for permanent neonatal diabetes with subclinical exocrine deficiency.
A novel hypomorphic PDX1 mutation responsible for permanent neonatal diabetes with subclinical exocrine deficiency.
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作者：
Nicolino M;Claiborn KC;Senée V;Boland A;Stoffers DA;Julier C
已经证明，负责单基因型糖尿病的基因对于理解涉及β细胞发育和功能的关键机制非常有价值。对选定的家系进行遗传学研究是鉴定这些基因的有力策略。我们研究了一个近亲家庭，两个堂兄弟受到新生儿糖尿病的影响，他们的四个父母有一个共同的祖先，提示一个完全外显隐性突变。我们对该家族进行了遗传学研究，对患者和四位父母进行了详细的临床和生化调查，并对新突变进行了生化和功能研究。我们在这两名患者的胰腺和十二指肠同源框1基因（PDX1，IPF1）中发现了一种新的突变，该突变在纯合状态下与糖尿病分离。该突变导致PDX1同源结构域中的E178G取代。与其他报道的导致新生儿糖尿病和胰腺发育不全的PDX1突变相反，E178G突变的纯合性与胰腺外分泌功能不全的临床体征无关。此外，四个杂合子父母没有糖尿病，并显示正常的葡萄糖耐量。然而，生化研究显示，亚临床外分泌胰腺功能不全的患者和轻微减少胰岛素分泌的杂合子父母。E178G突变导致Pdx 1反式激活减少，尽管正常的核定位，表达水平和染色质占有率。这项研究拓宽了PDX1突变的临床谱，并证明即使在没有胰腺外分泌表现的情况下，也可以在新生儿糖尿病患者中筛查该基因。
Genes responsible for monogenic forms of diabetes have proven very valuable for understanding key mechanisms involved in β-cell development and function. Genetic study of selected families is a powerful strategy to identify such genes. We studied a consanguineous family with two first cousins affected by neonatal diabetes; their four parents had a common ancestor, suggestive of a fully penetrant recessive mutation. We performed genetic studies of the family, detailed clinical and biochemical investigations of the patients and the four parents, and biochemical and functional studies of the new mutation. We found a novel mutation in the pancreatic and duodenal homeobox 1 gene (PDX1, IPF1) in the two patients, which segregated with diabetes in the homozygous state. The mutation resulted in an E178G substitution in the PDX1 homeodomain. In contrast to other reported PDX1 mutations leading to neonatal diabetes and pancreas agenesis, homozygosity for the E178G mutation was not associated with clinical signs of exocrine pancreas insufficiency. Further, the four heterozygous parents were not diabetic and displayed normal glucose tolerance. Biochemical studies, however, revealed subclinical exocrine pancreas insufficiency in the patients and slightly reduced insulin secretion in the heterozygous parents. The E178G mutation resulted in reduced Pdx1 transactivation despite normal nuclear localization, expression level, and chromatin occupancy. This study broadens the clinical spectrum of PDX1 mutations and justifies screening of this gene in neonatal diabetic patients even in the absence of exocrine pancreas manifestations.
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