Functions of CNKSR2 and Its Association with Neurodevelopmental Disorders

Abstract

The Connector Enhancer of Kinase Suppressor of Ras-2 (CNKSR2), also known as CNK2 or MAGUIN, is a scaffolding molecule that contains functional protein binding domains: Sterile Alpha Motif (SAM) domain, Conserved Region in CNK (CRIC) domain, PSD-95/Dlg-A/ZO-1 (PDZ) domain, Pleckstrin Homology (PH) domain, and C-terminal PDZ binding motif. CNKSR2 interacts with different molecules, including RAF1, ARHGAP39, and CYTH2, and regulates the Mitogen-Activated Protein Kinase (MAPK) cascade and small GTPase signaling. CNKSR2 has been reported to control the development of dendrite and dendritic spines in primary neurons. CNKSR2 is encoded by the CNKSR2 gene located in the X chromosome. CNKSR2 is now considered as a causative gene of the Houge type of X-linked syndromic mental retardation (MRXHG), an X-linked Intellectual Disability (XLID) that exhibits delayed development, intellectual disability, early-onset seizures, language delay, attention deficit, and hyperactivity. In this review, we summarized molecular features, neuronal function, and neurodevelopmental disorder-related variations of CNKSR2.

Hemizygous splicing variant in CNKSR2 results in X‐linked intellectual developmental disorder

“…The splicing variant was not observed in the gnomAD, ExAC, or ClinVar databases. Moreover, five other splicing variants of CNKSR2 were reported (Ito & Nagata, 2022), one in the CRIC domain around the Nterminus and the other located around the PH domain (Figure 1d). c.1657+1G>A in our patient was classified as likely pathogenic according to the ACMG guidelines.…”

Case report: Phenotype expansion and analysis of TRIO and CNKSR2 variations

“…Although phenotypic variability complicates the diagnosis of NDDs caused by RAC1-regulating genes, there is a significant clinical overlap in TRIO, CNKSR2 , and RAC1 . About 30 patients with TRIO pathogenic variations, 33 male cases with CNKSR2 pathogenic variations and seven cases carrying RAC1 pathogenic variations have been reported in the literature thus far ( 7 , 10 – 12 , 14 , 16 , 18 ).…”

“…CNKSR2 is a causative gene of the Houge type of X-linked syndromic intellectual developmental disorder. Most of the affected men described in the literature exhibited a consistent clinical phenotype of ID, developmental delay, language deficits, and early onset epilepsy ( 13 , 14 ). However, phenotypic variability complicates the diagnosis of NDDs caused by RAC1-regulating genes.…”

Pathophysiological Mechanism of Neurodevelopmental Disorders—Overview

“…CNKSR2 interacts with different molecules and regulates the MAP kinase (mitogen-activated protein kinase) cascade and Rho family small GTPase signaling. Ito and Nagata reviewed the possible pathophysiological mechanism of XLID by disrupting CNKSR2 functions, and summarized molecular features, neuronal function and NDD-related variations of CNKSR2 [ 5 ].…”