KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes
KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes
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DOI：
10.1002/humu.20124
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发表时间：
2005-01-01
期刊：
影响因子：
3.9
通讯作者：
Barbetti, F
中科院分区：
文献类型：
--
作者：
Massa, O;Iafusco, D;Barbetti, F
永久性新生儿糖尿病（PNDM）是一种罕见疾病，其特征是严重高血糖，从发病开始就持续需要胰岛素治疗。葡萄糖激酶（GCK）完全缺乏可导致PNDM；然而，大多数 PNDM 患者的遗传病因尚不清楚。最近，在 PNDM 患者中发现了编码 Kir6.2（胰腺 P 细胞 ATP 依赖性钾 (K-ATP) 通道的孔形成亚基）的 KCNJ11 杂合激活突变。 K-ATP 通道的关闭通过改变导致胰岛素胞吐作用的静息膜电位，在胰岛素分泌中发挥关键作用。我们对 12 名意大利 PNDM 患者（出生后 3 个月内发病）和 6 名在出生第一年诊断出的非自身免疫性、需要胰岛素的糖尿病患者进行了 KCNJ11 基因筛查。在第 3 天至 182 天之间诊断的 8 名糖尿病患者中发现了 5 种不同的杂合突变：c.149G>C (p.R50P)、c.175G>A (p.V59M)、C.509A>G (p.K170R)、c.510G>C (p.K170N) 和 c.601C>T (p.R201C)。 Arg50 和 Lys170 残基是新的。如之前报道的，四名患者还出现运动和/或发育迟缓。我们得出的结论是，KCNJ11 突变是 PNDM 的常见原因，无论是单独的还是与发育迟缓相关。对于具有 KCNJ11 和 EIF2AK3 突变的个体，非自身免疫性起源的永久性糖尿病可能会在出生后 6 个月内出现。因此，我们建议将首字母缩略词 PNDM 替换为更全面的婴儿期永久性糖尿病 (PDMI)，并将其与基因产物（例如 GCK、PDMI、KCNJ11-PDMI）联系起来，以避免与早发性自身免疫 1 型糖尿病患者混淆。 (C) 2004 Wiley-Liss, Inc.
Permanent neonatal diabetes mellitus (PNDM) is a rare condition characterized by severe hyperglycemia constantly requiring insulin treatment from its onset. Complete deficiency of glucokinase (GCK) can cause PNDM; however, the genetic etiology is unknown in most PNDM patients. Recently, heterozygous activating mutations of KCNJ11, encoding Kir6.2, the pore forming subunit of the ATP-dependent potassium (K-ATP) channel of the pancreatic P,cell, were found in patients With PNDM. Closure of the K-ATP channel exerts a pivotal role in insulin secretion by modifying the resting membrane potential that leads to insulin exocytosis. We screened the KCNJ11 gene in 12 Italian patients with PNDM (onset within 3 months from birth) and in six patients with non-autoimmune, insulin-requiring diabetes diagnosed during the first year of life. Five different heterozygous mutations were identified: c.149G>C (p.R50P), c.175G>A (p.V59M), C.509A>G (p.K170R), c.510G>C (p.K170N), and c.601C>T (p.R201C) in eight patients with diabetes diagnosed between day 3 and 182. Mutations at Arg50 and Lys170 residues are novel. Four patients also presented with motor and/or developmental delay as previously reported. We conclude that KCNJ11 mutations are a common cause of PNDM either in isolation or associated with developmental delay. Permanent diabetes of non autoimmune origin can present up to 6 months from birth in individuals with KCNJ11 and EIF2AK3 mutations. Therefore, we suggest that the acronym PNDM be replaced with the more comprehensive permanent diabetes mellitus of infancy (PDMI), linking it to the gene product (e.g., GCK,PDMI, KCNJ11-PDMI) to avoid confusion between patients with early-onset, autoimmune type 1 diabetes. (C) 2004 Wiley-Liss, Inc.