Masia Ricard, Koster Joseph C, Tumini Stefano, Chiarelli Francesco, Colombo Carlo, Nichols Colin G, Barbetti Fabrizio
Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Diabetes. 2007 Feb;56(2):328-36. doi: 10.2337/db06-1275.
Mutations in the pancreatic ATP-sensitive K(+) channel (K(ATP) channel) cause permanent neonatal diabetes mellitus (PNDM) in humans. All of the K(ATP) channel mutations examined result in decreased ATP inhibition, which in turn is predicted to suppress insulin secretion. Here we describe a patient with severe PNDM, which includes developmental delay and epilepsy, in addition to neonatal diabetes (developmental delay, epilepsy, and neonatal diabetes [DEND]), due to a G334D mutation in the Kir6.2 subunit of K(ATP) channel. The patient was wholly unresponsive to sulfonylurea therapy (up to 1.14 mg . kg(-1) . day(-1)) and remained insulin dependent. Consistent with the putative role of G334 as an ATP-binding residue, reconstituted homomeric and mixed WT+G334D channels exhibit absent or reduced ATP sensitivity but normal gating behavior in the absence of ATP. In disagreement with the sulfonylurea insensitivity of the affected patient, the G334D mutation has no effect on the sulfonylurea inhibition of reconstituted channels in excised patches. However, in macroscopic rubidium-efflux assays in intact cells, reconstituted mutant channels do exhibit a decreased, but still present, sulfonylurea response. The results demonstrate that ATP-binding site mutations can indeed cause DEND and suggest the possibility that sulfonylurea insensitivity of such patients may be a secondary reflection of the presence of DEND rather than a simple reflection of the underlying molecular basis.
胰腺ATP敏感性钾通道（KATP通道）的突变可导致人类永久性新生儿糖尿病（PNDM）。所有已检测的KATP通道突变都会导致ATP抑制作用减弱，进而预计会抑制胰岛素分泌。在此，我们描述了一名患有严重PNDM的患者，除新生儿糖尿病外，还伴有发育迟缓及癫痫（发育迟缓、癫痫和新生儿糖尿病[DEND]），其病因是KATP通道Kir6.2亚基发生了G334D突变。该患者对磺脲类药物治疗完全无反应（剂量高达1.14 mg·kg-1·day-1），仍依赖胰岛素。与G334作为ATP结合残基的假定作用一致，重组的同聚体和混合WT + G334D通道在无ATP时表现出ATP敏感性缺失或降低，但门控行为正常。与患病患者对磺脲类药物不敏感的情况不同，G334D突变对切除膜片上重组通道的磺脲类药物抑制作用没有影响。然而，在完整细胞的宏观铷外流试验中，重组的突变通道确实表现出磺脲类药物反应降低，但仍存在反应。结果表明，ATP结合位点突变确实可导致DEND，并提示此类患者对磺脲类药物不敏感可能是DEND存在的继发反映，而非潜在分子基础的简单反映。
