title: Keppen-Lubinsky syndrome is caused by mutations in the inwardly rectifying K+ channel encoded by KCNJ6.
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.
authors.affiliation: Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy. Electronic address: andrea.masotti@opbg.net.
authors.forename: Andrea
authors.initials: A
authors.lastname: Masotti
authors.affiliation: CRS4 Bioinformatics Laboratory, Parco Scientifico e Tecnologico POLARIS, 09010 Pula, Cagliari, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Uva
authors.affiliation: Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57105, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Davis-Keppen
authors.affiliation: 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.
authors.forename: Lina
authors.initials: L
authors.lastname: Basel-Vanagaite
authors.affiliation: Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva 49100, Israel.
authors.forename: Lior
authors.initials: L
authors.lastname: Cohen
authors.affiliation: Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Pisaneschi
authors.affiliation: Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Celluzzi
authors.affiliation: Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Bencivenga
authors.affiliation: BGI Shenzhen, Shenzhen 518083, China.
authors.forename: Mingyan
authors.initials: M
authors.lastname: Fang
authors.affiliation: BGI Tech Hong Kong, Hong Kong 518083, China.
authors.forename: Mingyu
authors.initials: M
authors.lastname: Tian
authors.affiliation: BGI Shenzhen, Shenzhen 518083, China. Electronic address: xuxun@genomics.cn.
authors.forename: Xun
authors.initials: X
authors.lastname: Xu
authors.affiliation: Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Cappa
authors.affiliation: Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D019465:Craniofacial Abnormalities / Q000235:genetics / Q000473:pathology; D017931:DNA Primers / Q000235:genetics; D002658:Developmental Disabilities / Q000235:genetics* / Q000473:pathology; D059472:Exome / Q000235:genetics; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion / Q000235:genetics; D013577:Syndrome
chemical_list: D017931:DNA Primers; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C094401:KCNJ6 protein, human