Open this publication in new window or tab >>Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Sorbonne Univ, Pitie Salpetriere Hosp, AP HP, Ctr Mol & Chromosomal Genet, 47-83 Blvd Hop, F-75013 Paris, France..
Sorbonne Univ, Pitie Salpetriere Hosp, AP HP, Ctr Mol & Chromosomal Genet, 47-83 Blvd Hop, F-75013 Paris, France..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Natl Inst Biotechnol & Genet Engn, Human Mol Genet Lab, Faisalabad 38000, Pakistan..
Natl Inst Biotechnol & Genet Engn, Human Mol Genet Lab, Faisalabad 38000, Pakistan..
Yokohama City Univ, Dept Human Genet, Grad Sch Med, Yokohama, Kanagawa 2360004, Japan.;Yokohama City Univ Med, Clin Genet Dept, Yokohama, Kanagawa 2360004, Japan..
Osaka Univ, Dept Pediat, Grad Sch Med, Suita, Osaka 5650871, Japan..
NHO Shizuoka Inst Epilepsy & Neurol Disorders, Natl Epilepsy Ctr, Shizuoka 4208688, Japan..
Showa Univ, Dept Pediat, Sch Med, Tokyo 1428666, Japan..
Osaka Univ, Res Inst Microbial Dis, Suita, Osaka 5650871, Japan..
PMAS Arid Agr Univ, Univ Inst Biochem & Biotechnol, Rawalpindi 46301, Pakistan..
Univ Punjab, Sch Biol Sci, Lahore 54590, Pakistan..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Rostedt Punga: Clinical Neurophysiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Yokohama City Univ, Dept Human Genet, Grad Sch Med, Yokohama, Kanagawa 2360004, Japan..
Natl Inst Biotechnol & Genet Engn, Human Mol Genet Lab, Faisalabad 38000, Pakistan.;Aga Khan Univ, Dept Biol & Biomed Sci, Karachi 74000, Pakistan..
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
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2021 (English)In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 108, no 4, p. 739-748Article in journal (Refereed) Published
Abstract [en]
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.
Place, publisher, year, edition, pages
Cell PressCELL PRESS, 2021
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-442185 (URN)10.1016/j.ajhg.2021.02.015 (DOI)000636658200015 ()33711248 (PubMedID)
Funder
Swedish Research Council, 2015-02424Swedish Research Council, 2020-01947The Swedish Brain Foundation, FO2019-0210The Swedish Brain Foundation, FO2020-0171Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceM Borgströms stiftelse för ärftlighetsforskning
2021-05-172021-05-172024-01-15Bibliographically approved