Heterozygous Variants in PLCG1 Affect Hearing, Vision, Cardiac, and Immune Function

Authors

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

Language

English

Publication Date

8-27-2025

Journal

eLife

DOI

10.7554/eLife.95887

PMID

40862571

PMCID

PMC12387771

PubMedCentral® Posted Date

8-27-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Phospholipase C isozymes (PLCs) hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP₂) into inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG), important signaling molecules involved in many cellular processes including Ca²⁺ 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 Ca²⁺ 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.

Research organism: D. melanogaster, Human

Keywords

Humans, Animals, Male, Female, Heterozygote, Phospholipase C gamma, Mutation, Missense, Adult, Vision, Ocular, Drosophila melanogaster

Published Open-Access

yes

Recommended Citation

Ma, Mengqi; Zheng, Yiming; Deng, Mingxi; et al., "Heterozygous Variants in PLCG1 Affect Hearing, Vision, Cardiac, and Immune Function" (2025). Duncan NRI Faculty and Staff Publications. 139.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/139