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.

Figure 1

Pedigree of the Three Study Families and KCNJ6 (GIRK2) Details (A) Cytogenetic localization of KCNJ6 (GIRK2). (B) Pedigree of the three families examined. (C) Photographs of the three individuals. (D) Sanger sequencing of the mutated regions confirms the findings of next-generation sequencing in the three individuals.

Figure 2

Protein Modeling (A) Crystal structure of KCNJ6 (GIRK2) (left) and a magnification of the K⁺ selectivity filter (right). The protein (Protein Data Bank accession number 3SYO) is shown in ribbon form, whereas the four subunits are colored in blue (chain A), green (chain B), yellow (chain C), and red (chain D). (B) The selectivity filter of the missense mutation and the deletion have been modeled and compared to the wild-type channel. The missense mutation determines the substitution of Ser154 instead of Gly154 residue within the channel, whereas the deletion leads to a shortening of the channel and a widening of the inner base of the K⁺ filter.