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Hum Genomics. 2019 Oct 22;13(1):53. doi: 10.1186/s40246-019-0236-0.

Identification and functional characterization of two novel mutations in KCNJ10 and PI4KB in SeSAME syndrome without electrolyte imbalance.

Author information

1
Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, 560029, India.
2
National Centre for Biological Sciences, Tata Institute for Fundamental Research, Bangalore, India.
3
Department of Speech Pathology and Audiology, National Institute of Mental Health and Neurosciences, Bangalore, India.
4
Department of Neuroimaging and Interventional Radiology, National Institute of Mental Health and Neurosciences, Bangalore, India.
5
Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India.
6
Department of Biophysics, National Institute of Mental Health and Neurosciences, Bangalore, India.
7
Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, 560029, India. kramkrishnak@gmail.com.

Abstract

BACKGROUND:

Dysfunction in inwardly rectifying potassium channel Kir4.1 has been implicated in SeSAME syndrome, an autosomal-recessive (AR), rare, multi-systemic disorder. However, not all neurological, intellectual disability, and comorbid phenotypes in SeSAME syndrome can be mechanistically linked solely to Kir4.1 dysfunction.

METHODS:

We therefore performed whole-exome sequencing and identified additional genetic risk-elements that might exert causative effects either alone or in concert with Kir4.1 in a family diagnosed with SeSAME syndrome.

RESULTS:

Two variant prioritization pipelines based on AR inheritance and runs of homozygosity (ROH), identified two novel homozygous variants in KCNJ10 and PI4KB and five rare homozygous variants in PVRL4, RORC, FLG2, FCRL1, NIT1 and one common homozygous variant in HSPA6 segregating in all four patients. The novel mutation in KCNJ10 resides in the cytoplasmic domain of Kir4.1, a seat of phosphatidylinositol bisphosphate (PIP2) binding. The mutation altered the subcellular localization and stability of Kir4.1 in patient-specific lymphoblastoid cells (LCLs) compared to parental controls. Barium-sensitive endogenous K+ currents in patient-specific LCLs using whole-cell patch-clamp electrophysiology revealed membrane depolarization and defects in inward K+ ion conductance across the membrane, thereby suggesting a loss-of-function effect of KCNJ10 variant.

CONCLUSION:

Altogether, our findings implicate the role of new genes in SeSAME syndrome without electrolyte imbalance and thereby speculate the regulation of Kir4.1 channel activity by PIP2 and integrin-mediated adhesion signaling mechanisms.

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