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Mutations in phospholipase C eta-1 (PLCH1) are associated with holoprosencephaly

Lookup NU author(s): Dr Steven LisgoORCiD, Emerita Professor Susan Lindsay

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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).


Abstract

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ. Background: Holoprosencephaly is a spectrum of developmental disorder of the embryonic forebrain in which there is failed or incomplete separation of the prosencephalon into two cerebral hemispheres. To date, dominant mutations in sonic hedgehog (SHH) pathway genes are the predominant Mendelian causes, and have marked interfamilial and intrafamilial phenotypical variabilities. Methods: We describe two families in which offspring had holoprosencephaly spectrum and homozygous predicted-deleterious variants in phospholipase C eta-1 (PLCH1). Immunocytochemistry was used to examine the expression pattern of PLCH1 in human embryos. We used SHH as a marker of developmental stage and of early embryonic anatomy. Results: In the first family, two siblings had congenital hydrocephalus, significant developmental delay and a monoventricle or fused thalami with a homozygous PLCH1 c.2065C>T, p.(Arg689∗) variant. In the second family, two siblings had alobar holoprosencephaly and cyclopia with a homozygous PLCH1 c.4235delA, p.(Cys1079ValfsTer16) variant. All parents were healthy carriers, with no holoprosencephaly spectrum features. We found that the subcellular localisation of PLCH1 is cytoplasmic, but the p.(Cys1079ValfsTer16) variant was predominantly nuclear. Human embryo immunohistochemistry showed PLCH1 to be expressed in the notorcord, developing spinal cord (in a ventral to dorsal gradient), dorsal root ganglia, cerebellum and dermatomyosome, all tissues producing or responding to SHH. Furthermore, the embryonic subcellular localisation of PLCH1 was exclusively cytoplasmic, supporting protein mislocalisation contributing to the pathogenicity of the p.(Cys1079ValfsTer16) variant. Conclusion: Our data support the contention that PLCH1 has a role in prenatal mammalian neurodevelopment, and deleterious variants cause a clinically variable holoprosencephaly spectrum phenotype.


Publication metadata

Author(s): Drissi I, Fletcher E, Shaheen R, Nahorski M, Alhashem AM, Lisgo S, Fernandez-Jaen A, Schon K, Tlili-Graiess K, Smithson SF, Lindsay S, Sharpe HJ, Alkuraya FS, Woods G

Publication type: Article

Publication status: Published

Journal: Journal of Medical Genetics

Year: 2022

Volume: 59

Issue: 4

Pages: 358-365

Print publication date: 01/04/2022

Online publication date: 05/04/2021

Acceptance date: 24/01/2021

Date deposited: 30/11/2023

ISSN (print): 0022-2593

ISSN (electronic): 1468-6244

Publisher: BMJ Publishing Group

URL: https://doi.org/10.1136/jmedgenet-2020-107237

DOI: 10.1136/jmedgenet-2020-107237

Data Access Statement: All data relevant to the study are included in the article or uploaded as supplementary information. GW's mail address: cw347@cam.ac.ukAddress: Cambridge Institute for Medical Research, University of Cambridge, Keith Peters Building, Addenbrookes Hospital, Hills Rd, Cambridge CB2 0QQ, UK.Website: https://www.cimr.cam.ac.uk/research/principal-investigators/woods.


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Funding

Funder referenceFunder name
099175/Z/12/ZWellcome Trust
MR/R006237/1Medical Research Council (MRC)
MRC
Wellcome Trust

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