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

Andrea Masotti, Paolo Uva, Laura Davis-Keppen, Lina Basel-Vanagaite, Lior Cohen, Elisa Pisaneschi, Antonella Celluzzi, Paola Bencivenga, Mingyan Fang, Mingyu Tian, Xun Xu, Marco Cappa, Bruno Dallapiccola

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)295-300
Number of pages6
JournalAmerican Journal of Human Genetics
Volume96
Issue number2
DOIs
Publication statusPublished - Feb 5 2015

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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