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.

Congenital generalized lipodystrophies—new insights into metabolic dysfunction

“…[12][13][14][15] By contrast, the other types of lipodystrophy-mandibuloacral dysplasia, autoinflammatory lipodystrophy, progeroid syndromes associated lipodystrophy, SHORT syndrome associated lipodystrophy and Keppen-Lubinsky syndrome associ ated lipodystrophy-are extremely rare and in total each subtype has been reported in no more than 30 patients (Box 1). 10,11,[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] However, FPLD has autosomal dominant inheritance and some patients with subtle loss of fat from the extremities might not receive an accurate diagnosis; therefore, the prevalence of this lipodystrophy might be higher than is reported. CGL has the most extreme pheno type with loss of nearly all the body fat at birth ( Figure 1) and early development of metabolic complications in childhood.…”

Evidence that increased Kcnj6 gene dose is necessary for deficits in behavior and dentate gyrus synaptic plasticity in the Ts65Dn mouse model of Down syndrome

“…Consistent with this view, a missense mutation of Kcnj6 altering the pore-forming domain of the potassium channel is responsible for the ‘ weaver’ phenotype, characterized by abnormal development of the cerebellum (Patil et al, 1995). In addition, a heterozygous deletion of three nucleotides or a missense mutation introducing a single amino acid change from glycine to serine in Kir3.2 subunit causes the Keppen-Lubinsky syndrome, a rare genetic disorder characterized by severe developmental delay, intellectual disability, and microcephaly (Basel-Vanagaite et al, 2009; Masotti et al, 2015). …”

Genome‐wide analysis reveals conserved transcriptional responses downstream of resting potential change in Xenopus embryos, axolotl regeneration, and human mesenchymal cell differentiation

“…), as well as being responsible for several classes of developmental malformation in humans (Galanopoulou ; Tristani‐Firouzi & Etheridge ; Masotti et al. ). Bioelectric signals can trigger the formation of whole ectopic organs, such as in the case of eye development (Pai et al.…”