Heterozygous variants in PLCG1 affect hearing, vision, cardiac, and immune function

Phospholipase C isozymes (PLCs) hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP 2 ) into inositol 1,4,5-trisphosphate (IP 3 ) and diacylglycerol (DAG), important signaling molecules involved in many cellular processes including Ca 2+ release from the endoplasmic reticulum (ER). PLCG1 encodes the PLCγ1 isozyme that is broadly expressed. Hyperactive somatic mutations of PLCG1 are observed in multiple cancers, but only one germline variant has been reported. Here, we describe seven individuals with heterozygous missense variants in PLCG1 [p.(Asp1019Gly), p.(His380Arg), p.(Asp1165Gly), and p.(Leu597Phe)] who present with hearing impairment (5/7), ocular pathology (4/7), cardiac septal defects (3/6), and various immunological issues (5/7). To model these variants in vivo , we generated the analogous variants in the Drosophila ortholog, small wing ( sl ). We created a null allele sl T2A and assessed its expression pattern. sl is broadly expressed, including wing discs, eye discs, and a subset of neurons and glia. sl T2A mutant flies exhibit wing size reductions, ectopic wing veins, and supernumerary photoreceptors. We document that mutant flies also exhibit a reduced lifespan and age-dependent locomotor defects. Expressing wild-type sl in sl T2A mutant flies rescues the loss-of-function phenotypes, whereas the variants increase lethality. Ectopic expression of an established hyperactive PLCG1 variant, p.(Asp1165His) in the wing pouch causes elevated Ca 2+ activity and severe wing phenotypes. These phenotypes are also observed when the p.(Asp1019Gly) or p.(Asp1165Gly) variants are overexpressed in the wing pouch, arguing that these are gain-of-function variants. However, the wing phenotypes associated with p.(His380Arg) or p.(Leu597Phe) overexpression are either mild or only partially penetrant. Our data suggest that the heterozygous missense variants reported here affect protein function differentially and contribute to the clinical features observed in the affected individuals.

Authors

Institutions

Publication Details

Journal
eLife
Published
2025-08-27
DOI
https://doi.org/10.7554/elife.95887.3
Primary Topic
Congenital heart defects research
Type
article
Field-Weighted Citation Impact
0.00

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Heterozygous variants in PLCG1 affect hearing, vision, cardiac, and immune function

Elizabeth Blue, Paolo Prontera, Xueyang Pan, Mengqi Ma et al.
1 links
eLife
Congenital heart defects research
article

Heterozygous variants in PLCG1 affect hearing, vision, cardiac, and immune function

Elizabeth Blue, Paolo Prontera, Xueyang Pan, Mengqi Ma, Barbara Mandriani, Kim C. Worley, Hugo J. Bellen, Giuseppe Merla, Lindsay C. Burrage, Seema R. Lalani, Sandrine Marlin, Catherine Otten, Debdeep Dutta, Aimee Allworth, Shenzhao Lu, Lauren S. Blieden, Jill Anne Rosenfeld, Yiming Zheng, Jérémie Rosain, Shinya Yamamoto, Mingxi Deng, Pierre Blanc, Ian A. Glass, David Li‐Kroeger, Michael F. Wangler, Wei-Liang Chen, Xi Luo, Jingheng Chen, Michelle Etoundi
article en

Abstract

Phospholipase C isozymes (PLCs) hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP 2 ) into inositol 1,4,5-trisphosphate (IP 3 ) and diacylglycerol (DAG), important signaling molecules involved in many cellular processes including Ca 2+ release from the endoplasmic reticulum (ER). PLCG1 encodes the PLCγ1 isozyme that is broadly expressed. Hyperactive somatic mutations of PLCG1 are observed in multiple cancers, but only one germline variant has been reported. Here, we describe seven individuals with heterozygous missense variants in PLCG1 [p.(Asp1019Gly), p.(His380Arg), p.(Asp1165Gly), and p.(Leu597Phe)] who present with hearing impairment (5/7), ocular pathology (4/7), cardiac septal defects (3/6), and various immunological issues (5/7). To model these variants in vivo , we generated the analogous variants in the Drosophila ortholog, small wing ( sl ). We created a null allele sl T2A and assessed its expression pattern. sl is broadly expressed, including wing discs, eye discs, and a subset of neurons and glia. sl T2A mutant flies exhibit wing size reductions, ectopic wing veins, and supernumerary photoreceptors. We document that mutant flies also exhibit a reduced lifespan and age-dependent locomotor defects. Expressing wild-type sl in sl T2A mutant flies rescues the loss-of-function phenotypes, whereas the variants increase lethality. Ectopic expression of an established hyperactive PLCG1 variant, p.(Asp1165His) in the wing pouch causes elevated Ca 2+ activity and severe wing phenotypes. These phenotypes are also observed when the p.(Asp1019Gly) or p.(Asp1165Gly) variants are overexpressed in the wing pouch, arguing that these are gain-of-function variants. However, the wing phenotypes associated with p.(His380Arg) or p.(Leu597Phe) overexpression are either mild or only partially penetrant. Our data suggest that the heterozygous missense variants reported here affect protein function differentially and contribute to the clinical features observed in the affected individuals.

eLifeVol. 13
Hôpital Necker-Enfants Malades (FR), Baylor College of Medicine (US), University of Washington (US), Casa Sollievo della Sofferenza (IT), University of Washington Medical Center (US), Azienda Ospedaliera di Perugia (IT), Assistance Publique – Hôpitaux de Paris (FR), Seattle Children's Hospital (US), Neurological Research Institute (US), Brotman Baty Institute (US), Texas Children's Hospital (US), Institut des Maladies Génétiques Imagine (FR), University of Bari Aldo Moro (IT), University of Naples Federico II (IT)
Huffington Foundation, National Human Genome Research Institute, National Institute of Neurological Disorders and Stroke
Openalex Percentile: Top 80%
Congenital heart defects research
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.