HCFC1 loss-of-function mutations disrupt neuronal and neural progenitor cells of the developing brain

Human Molecular Genetics
Lachlan A JollyJozef Gecz

Abstract

Both gain- and loss-of-function mutations have recently implicated HCFC1 in neurodevelopmental disorders. Here, we extend our previous HCFC1 over-expression studies by employing short hairpin RNA to reduce the expression of Hcfc1 in embryonic neural cells. We show that in contrast to over-expression, loss of Hcfc1 favoured proliferation of neural progenitor cells at the expense of differentiation and promoted axonal growth of post-mitotic neurons. To further support the involvement of HCFC1 in neurological disorders, we report two novel HCFC1 missense variants found in individuals with intellectual disability (ID). One of these variants, together with three previously reported HCFC1 missense variants of unknown pathogenicity, were functionally assessed using multiple cell-based assays. We show that three out of the four variants tested result in a partial loss of HCFC1 function. While over-expression of the wild-type HCFC1 caused reduction in HEK293T cell proliferation and axonal growth of neurons, these effects were alleviated upon over-expression of three of the four HCFC1 variants tested. One of these partial loss-of-function variants disrupted a nuclear localization sequence and the resulting protein displayed reduced abili...Continue Reading

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Citations

Sep 4, 2015·American Journal of Medical Genetics. Part a·Giulia SeveriClaudio Graziano
Apr 28, 2017·Human Molecular Genetics·Anita M QuintanaTamim H Shaikh
Jun 3, 2017·American Journal of Human Genetics·Michele GabrieleBert B A de Vries
Jun 7, 2017·The Journal of Biological Chemistry·Anke P WillemsDirk J Lefeber
Jun 18, 2019·Developmental Neurobiology·Shilpi Minocha, Winship Herr
Jul 13, 2019·Proceedings of the National Academy of Sciences of the United States of America·Veronica M PravataDaan M F van Aalten
Jun 12, 2020·BMC Neuroscience·Victoria L CastroAnita M Quintana
Jun 25, 2021·Disease Models & Mechanisms·Thomas P ZwakaMarion Dejosez

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