Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K.
Genomic Programming of Beta-Cells Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, SpainCIBER de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain.
Diabetes. 2014 Aug;63(8):2888-94. doi: 10.2337/db14-0061. Epub 2014 Apr 2.
The GATA family zinc finger transcription factors GATA4 and GATA6 are known to play important roles in the development of the pancreas. In mice, both Gata4 and Gata6 are required for pancreatic development. In humans, GATA6 haploinsufficiency can cause pancreatic agenesis and heart defects. Congenital heart defects also are common in patients with GATA4 mutations and deletions, but the role of GATA4 in the developing human pancreas is unproven. We report five patients with deletions (n = 4) or mutations of the GATA4 gene who have diabetes and a variable exocrine phenotype. In four cases, diabetes presented in the neonatal period (age at diagnosis 1-7 days). A de novo GATA4 missense mutation (p.N273K) was identified in a patient with complete absence of the pancreas confirmed at postmortem. This mutation affects a highly conserved residue located in the second zinc finger domain of the GATA4 protein. In vitro studies showed reduced DNA binding and transactivational activity of the mutant protein. We show that GATA4 mutations/deletions are a cause of neonatal or childhood-onset diabetes with or without exocrine insufficiency. These results confirm a role for GATA4 in normal development of the human pancreas.
GATA 家族锌指转录因子 GATA4 和 GATA6 已知在胰腺发育中发挥重要作用。在小鼠中，Gata4 和 Gata6 都对胰腺发育至关重要。在人类中，GATA6 半合子不足可导致胰腺发育不全和心脏缺陷。GATA4 突变和缺失的患者也常伴有先天性心脏病，但 GATA4 在人胰腺发育中的作用尚未得到证实。我们报道了 5 例 GATA4 基因缺失（n=4）或突变的患者，这些患者患有糖尿病和可变的外分泌表型。在 4 例中，糖尿病在新生儿期（诊断时年龄为 1-7 天）出现。在一例胰腺完全缺失的患者中发现了一个新的 GATA4 错义突变（p.N273K），该患者在死后得到了证实。该突变影响 GATA4 蛋白第二个锌指结构域中高度保守的残基。体外研究表明，突变蛋白的 DNA 结合和转录激活活性降低。我们表明，GATA4 突变/缺失是导致新生儿或儿童期起病的糖尿病伴或不伴外分泌不足的原因。这些结果证实了 GATA4 在人类胰腺正常发育中的作用。
