2. Academic Validation
  3. Keppen-Lubinsky syndrome is caused by mutations in the inwardly rectifying K+ channel encoded by KCNJ6

Keppen-Lubinsky syndrome is caused by mutations in the inwardly rectifying K+ channel encoded by KCNJ6

  • Am J Hum Genet. 2015 Feb 5;96(2):295-300. doi: 10.1016/j.ajhg.2014.12.011.
Andrea Masotti 1,  Paolo Uva 2,  Laura Davis-Keppen 3,  Lina Basel-Vanagaite 4,  Lior Cohen 5,  Elisa Pisaneschi 6,  Antonella Celluzzi 6,  Paola Bencivenga 6,  Mingyan Fang 7,  Mingyu Tian 8,  Xun Xu 9,  Marco Cappa 6,  Bruno Dallapiccola 6
Affiliations

Affiliations

  • 1 Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy. Electronic address: [email protected].
  • 2 CRS4 Bioinformatics Laboratory, Parco Scientifico e Tecnologico POLARIS, 09010 Pula, Cagliari, Italy.
  • 3 Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57105, USA.
  • 4 Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petah Tikva 49202, Israel; Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva 49100, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva 49100, Israel.
  • 5 Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva 49100, Israel.
  • 6 Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy.
  • 7 BGI Shenzhen, Shenzhen 518083, China.
  • 8 BGI Tech Hong Kong, Hong Kong 518083, China.
  • 9 BGI Shenzhen, Shenzhen 518083, China. Electronic address: [email protected].
PMID: 25620207 DOI: 10.1016/j.ajhg.2014.12.011
Abstract

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.

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