Study explains why KIAA1202 mutations contribute to epilepsy and intellectual disability

Published in Nature Communications, a study sheds light on why mutations in KIAA1202 contribute to epilepsy and intellectual disability. The study is led by the Institute of Neuroscience of the National Research Council, the Università di Milano, Istituto Scientifico Ospedale San Raffaele, and the University of Modena and Reggio Emilia in the Italy, the University College London in the UK, University of Pittsburgh in the USA, Max Planck Institute for Molecular Genetics in the Germany, University of Basel in the Switzerland.

Intellectual disability (ID), once called mental retardation, is a generalized neurodevelopmental disorder characterized by limitations in intellectual functioning and in adaptive behavior. ID is estimated to affect 2-3% of the general population. This disability often has their onset before the age of 18, and patients typically have problems with everyday functions such as cognitive, language, motor, and social activities.

Epilepsy, a neurological disorder that causes people to have seizures, occurs more frequently in people with ID than in the general population. Previous studies have shown that some cases of epilepsy and intellectual disability are associated with mutations in a gene called KIAA1202. But the underlying mechanism remains unclear.

The KIAA1202 gene provides instructions for making a protein called Shrm4, which is only found in polarized tissues. The function of Shrm4 in the brain is unclear. The researchers demonstrated that Shrm4 plays a role in synaptogenesis and in maintaining GABABR-mediated inhibition. Without Shrm4, GABABR (GABAB receptors) are unable to reach synapses and exert their function.

GABAB receptors are metabotropic transmembrane receptors for GABA, the chief inhibitory neurotransmitter in the mammalian central nervous system. GABABR-mediated inhibition is crucial for synaptic plasticity, and dysfunction of these receptors is found in different neurological diseases.

The Shroom(Shrm) protein family has a key role in cytoskeletal organization. There are four types of Shrms proteins (Shrm1-4), which are localized to polarized tissues, such as neurons. In mice and humans, the Shrm family of proteins consists of Shrm2, Shrm3, and Shrm4. Previous studies have demonstrated that disruptions in Shrm4, which is encoded by the KIAA1202 gene (Xp11.2), is associated with mild-to-severe intellectual disability (ID) and increased susceptibility to seizures among humans. Now this study provide clear evidence that “disrupting Shrm4 expression are severe and manifest by increased anxiety, social behaviours impairments and a predisposition towards epilepsy.”

The study involves various analytical methods such as Western blots, GST pull-down and immunoprecipitation, Immunofluorescence and surface staining, Immunohistochemistry, and Immuno-Electron Microscopy. In these methods, various antibodies are used. By the way, CusAb is a manufacturer of bioproducts, including Shroom proteins, and Recombinant Cd63.