Masotti Andrea, Uva Paolo, Davis-Keppen Laura, Basel-Vanagaite Lina, Cohen Lior, Pisaneschi Elisa, Celluzzi Antonella, Bencivenga Paola, Fang Mingyan, Tian Mingyu, Xu Xun, Cappa Marco, Dallapiccola Bruno
Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy.
CRS4 Bioinformatics Laboratory, Parco Scientifico e Tecnologico POLARIS, 09010 Pula, Cagliari, Italy.
Am J Hum Genet. 2015 Feb 5;96(2):295-300. doi: 10.1016/j.ajhg.2014.12.011. Epub 2015 Jan 22.
Keppen-Lubinsky syndrome (KPLBS) is a rare disease mainly characterized by severe developmental delay and intellectual disability, microcephaly, large prominent eyes, a narrow nasal bridge, a tented upper lip, a high palate, an open mouth, tightly adherent skin, an aged appearance, and severe generalized lipodystrophy. We sequenced the exomes of three unrelated individuals affected by KPLBS and found de novo heterozygous mutations in KCNJ6 (GIRK2), which encodes an inwardly rectifying potassium channel and maps to the Down syndrome critical region between DIRK1A and DSCR4. In particular, two individuals shared an in-frame heterozygous deletion of three nucleotides (c.455_457del) leading to the loss of one amino acid (p.Thr152del). The third individual was heterozygous for a missense mutation (c.460G>A) which introduces an amino acid change from glycine to serine (p.Gly154Ser). In agreement with animal models, the present data suggest that these mutations severely impair the correct functioning of this potassium channel. Overall, these results establish KPLBS as a channelopathy and suggest that KCNJ6 (GIRK2) could also be a candidate gene for other lipodystrophies. We hope that these results will prompt investigations in this unexplored class of inwardly rectifying K(+) channels.
凯彭-卢宾斯基综合征（KPLBS）是一种罕见疾病，主要特征为严重发育迟缓、智力残疾、小头畸形、眼睛大且突出、鼻梁狭窄、上唇呈帐篷状、腭高、嘴巴张开、皮肤紧密粘连、面容苍老以及严重的全身性脂肪营养不良。我们对三名患KPLBS的无关个体的外显子组进行了测序，在KCNJ6（GIRK2）中发现了新生杂合突变，该基因编码内向整流钾通道，定位于DIRK1A和DSCR4之间的唐氏综合征关键区域。具体而言，两名个体共享了三个核苷酸的框内杂合缺失（c.455_457del），导致一个氨基酸缺失（p.Thr152del）。第三名个体为错义突变（c.460G>A）的杂合子，该突变导致氨基酸从甘氨酸变为丝氨酸（p.Gly154Ser）。与动物模型一致，目前的数据表明这些突变严重损害了该钾通道的正常功能。总体而言，这些结果将KPLBS确立为一种通道病，并表明KCNJ6（GIRK2）也可能是其他脂肪营养不良的候选基因。我们希望这些结果将促使对这一未被探索的内向整流K(+)通道类别进行研究。
