Monoallelic and bi-allelic variants in NCDN cause neurodevelopmental delay, intellectual disability, and epilepsy

Abstract

Neurochondrin (NCDN) is a cytoplasmatic neural protein of importance for neural growth, glutamate receptor (mGluR) signaling, and synaptic plasticity. Conditional loss of Ncdn in mice neural tissue causes depressive-like behaviors, impaired spatial learning, and epileptic seizures. We report on NCDN missense variants in six affected individuals with variable degrees of developmental delay, intellectual disability (ID), and seizures. Three siblings were found homozygous for a NCDN missense variant, whereas another three unrelated individuals carried different de novo missense variants in NCDN. We assayed the missense variants for their capability to rescue impaired neurite formation in human neuroblastoma (SH-SY5Y) cells depleted of NCDN. Overexpression of wild-type NCDN rescued the neurite-phenotype in contrast to expression of NCDN containing the variants of affected individuals. Two missense variants, associated with severe neurodevelopmental features and epilepsy, were unable to restore mGluR5-induced ERK phosphorylation. Electrophysiological analysis of SH-SY5Y cells depleted of NCDN exhibited altered membrane potential and impaired action potentials at repolarization, suggesting NCDN to be required for normal biophysical properties. Using available transcriptome data from human fetal cortex, we show that NCDN is highly expressed in maturing excitatory neurons. In combination, our data provide evidence that bi-allelic and de novo variants in NCDN cause a clinically variable form of neurodevelopmental delay and epilepsy, highlighting a critical role for NCDN in human brain development.

Gene pseudogenization in fertility-associated genes in cheetah (Acinonyx jubatus), a species with long-term low effective population size

“…Notable genes amongst these 22 include eight associated with male fertility (MOV10L1 (Fu et al, 2016), PHF7 (Cheng et al, 2023), ABHD10 (Smith and Eppig, 2009), CFAP119 (Iso-Touru et al, 2019), MARCHF6 (Smith and Eppig, 2009), MAGEB4 (Okutman et al, 2017), DEFB116 (Caballero-Campo et al, 2014;Zhang et al, 2018), and ARL13A (Schürmann et al, 2002)); immunity (DEFB116 (Schröder and Harder, 1999;Schneider et al, 2005;Dhople et al, 2006), ARL13A (Song and Perkins, 2018), and IGBP1C (Smith and Eppig, 2009)); cancer (SSX5 (Smith and McNeel, 2010), TNFAIP1 (Tian et al, 2015), PRSS3 (Hockla et al, 2012), SLC38A7 (Haratake et al, 2021), and HAS3 (Wang et al, 2022)); and developmental defects (NCDN (Fatima et al, 2021)).…”

Differential Methylation Profile in Fragile X Syndrome-Prone Offspring Mice after in Utero Exposure to Lactobacillus Reuteri

“…Among them were the Ncdn , the Agpat1 , the Dctn1 , the Fbx011 , the Emx2 , the Dcc gene, and the Gart genes, all encoding for proteins associated with seizures, abnormal hippocampal brain development ID, ASD, ADHD, anxiety, developmental delays, aggression, hyperactivity, altered social skills, delays in speech and language skills, and childhood epilepsy [ 46 , 51 , 66 , 67 ]. A number of identified genes were associated with ASD and listed in the SFARI database ( Table 1 , labeled with an asterisk).…”

A postzygotic de novo NCDN mutation identified in a sporadic FTLD patient results in neurochondrin haploinsufficiency and altered FUS granule dynamics

“…Missense variants were however reported in patients with a neurodevelopmental phenotype with epilepsy. One family exhibited a missense homozygous variant, with unaffected heterozygous parents, while 3 unrelated patients showed missense de novo variants with a more severe phenotype [ 18 ]. Functional analyses suggested a loss-of-function effect, the bi-allelic variant being most likely hypomorphic, and de novo variants affected NCDN function more severely.…”