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

Am J Hum Genet. 2021 Apr 1;108(4):739-748. doi: 10.1016/j.ajhg.2021.02.015.

Ambrin Fatima ¹, Jan Hoeber ¹, Jens Schuster ¹, Eriko Koshimizu ², Carolina Maya-Gonzalez ¹, Boris Keren ³, Cyril Mignot ³, Talia Akram ⁴, Zafar Ali ⁵, Satoko Miyatake ⁶, Junpei Tanigawa ⁷, Takayoshi Koike ⁸, Mitsuhiro Kato ⁹, Yoshiko Murakami ¹⁰, Uzma Abdullah ¹¹, Muhammad Akhtar Ali ¹², Rein Fadoul ¹, Loora Laan ¹, Casimiro Castillejo-López ¹, Maarika Liik ¹³, Zhe Jin ¹⁴, Bryndis Birnir ¹⁴, Naomichi Matsumoto ², Shahid M Baig ⁵, Joakim Klar ¹, Niklas Dahl ¹⁵

Affiliations

1 Department of Immunology, Genetics and Pathology, Uppsala University and Science for Life Laboratory, Box 815, 751 08 Uppsala, Sweden.
2 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
3 Center for Molecular and Chromosomal Genetics APHP, Sorbonne University, Pitié-Salpêtrière Hospital, 47-83 Boulevard de l'Hôpital, 75013 Paris, France.
4 Department of Immunology, Genetics and Pathology, Uppsala University and Science for Life Laboratory, Box 815, 751 08 Uppsala, Sweden; Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering, Faisalabad 38000, Pakistan.
5 Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering, Faisalabad 38000, Pakistan.
6 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan; Clinical Genetics Department, Yokohama City University Hospital, Yokohama, Kanagawa 236-0004, Japan.
7 Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
8 National Epilepsy Center, NHO Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka 420-8688, Japan.
9 Department of Pediatrics, Showa University School of Medicine, Tokyo 142-8666, Japan.
10 Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
11 University Institute of Biochemistry and Biotechnology, PMAS-Arid Agriculture University, Rawalpindi 46301, Pakistan.
12 School of Biological Sciences, University of the Punjab, Lahore 54590, Pakistan.
13 Unit of Clinical Neurophysiology, Uppsala University Hospital, 751 85 Uppsala, Sweden.
14 Department of Medical Cell Biology, Biomedical Centre, Uppsala University, 751 08 Uppsala, Sweden.
15 Department of Immunology, Genetics and Pathology, Uppsala University and Science for Life Laboratory, Box 815, 751 08 Uppsala, Sweden. Electronic address: [email protected].

PMID: 33711248 DOI: 10.1016/j.ajhg.2021.02.015

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.

Keywords

NCDN gene; de novo variant; epilepsy; intellectual disability; mGluR5 signaling; missense variant; neurite formation; neurodevelopmental delay; speech delay.

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