Mutations in phospholipase C eta-1 ( PLCH1 ) are associated with holoprosencephaly
| Autor: | Kalthoum Tlili-Graiess, Hayley J. Sharpe, Susan Lindsay, Emily V. Fletcher, Geoff Woods, Amal Alhashem, Katherine Schon, Ranad Shaheen, Michael S. Nahorski, Ichrak Drissi, Sarah F. Smithson, Fowzan S. Alkuraya, Steve Lisgo, Alberto Fernández-Jaén |
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| Přispěvatelé: | Drissi, Ichrak [0000-0002-8077-2101], Lisgo, Steve [0000-0001-5186-3971], Fernández-Jaén, Alberto [0000-0003-3306-9832], Alkuraya, Fowzan S [0000-0003-4158-341X], Woods, Geoff [0000-0002-8077-2101], Apollo - University of Cambridge Repository |
| Rok vydání: | 2021 |
| Předmět: |
Cerebellum
Immunocytochemistry cerebellar diseases medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Holoprosencephaly medicine Animals Humans Hedgehog Proteins genetics Sonic hedgehog Neurogenetics Genetics (clinical) ComputingMilieux_MISCELLANEOUS 030304 developmental biology Mammals Genetics 0303 health sciences Mutation biology congenital Embryo Cyclopia medicine.disease Phenotype medicine.anatomical_structure Type C Phospholipases biology.protein and neonatal diseases and abnormalities mutation hereditary 030217 neurology & neurosurgery |
| Popis: | Funder: NIHR Cambridge Biomedical Research centre 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. |
| Databáze: | OpenAIRE |
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