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

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; Undiagnosed Diseases Network; Ian A Glass; Jingheng Chen; Elizabeth Blue; Paolo Prontera; Jeremie Rosain; Sandrine Marlin; Seema R Lalani; Hugo J Bellen

doi:10.1101/2024.01.08.23300523

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

medRxiv [Preprint]. 2025 May 29:2024.01.08.23300523. doi: 10.1101/2024.01.08.23300523.

Authors

Mengqi Ma^{1

2}, Yiming Zheng^{1

2}, Mingxi Deng^{1

2}, Shenzhao Lu^{1

2}, Xueyang Pan¹, Xi Luo¹, Michelle Etoundi^{2

3}, David Li-Kroeger^{2

3}, Kim C Worley¹, Lindsay C Burrage¹, Lauren S Blieden⁴, Aimee Allworth⁵, Wei-Liang Chen⁵, Giuseppe Merla^{6

7}, Barbara Mandriani⁸, Catherine E Otten⁹, Pierre Blanc¹⁰, Jill A Rosenfeld¹, Debdeep Dutta^{1

2}, Shinya Yamamoto^{1

2}, Michael F Wangler^{1

2}; Undiagnosed Diseases Network; Ian A Glass^{5

11

12}, Jingheng Chen⁵, Elizabeth Blue^{5

12

13}, Paolo Prontera¹⁴, Jeremie Rosain^{15

16}, Sandrine Marlin^{17

18}, Seema R Lalani¹, Hugo J Bellen^{1

2}

Affiliations

¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
² Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA.
³ Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
⁴ The Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.
⁶ Laboratory of Regulatory & Functional Genomics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia 71013, Italy.
⁷ Department of Molecular Medicine & Medical Biotechnology, University of Naples Federico II, Naples 80131, Italy.
⁸ Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari 70121, Italy.
⁹ Department of Neurology, University of Washington and Seattle Children's Hospital, Seattle, WA 98195, USA.
¹⁰ SeqOIA Genomics Platform, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris 75014, France.
¹¹ Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA.
¹² Brotman Baty Institute, Seattle, WA 98195, USA.
¹³ Institute for Public Health Genetics, University of Washington, Seattle, WA 98195, USA.
¹⁴ Medical Genetics and Rare Diseases Unit, Hospital of Perugia, Perugia 06129, Italy.
¹⁵ Laboratory of Human Genetics of Infectious Diseases, Imagine Institute, Necker Hospital for Sick Children, Paris 75015, France.
¹⁶ Center for the Study of Immune Deficiencies, Necker-Enfants Malades Hospital, AP-HP Centre, University of Paris, Paris 75015, France.
¹⁷ Genetics of Rare Ophthalmological, Auditory and Mitochondrial Disorders, Inserm UMR_S1163, Imagine Institute, Paris 75015, France.
¹⁸ Reference Center for Genetic Deafness, Department of Genomic Medicine for Rare Diseases, Necker-Enfants Malades Hospital, AP-HP Centre, University of Paris, Paris 75015, France.

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.

Keywords: Drosophila; Phospholipase C; phenotypic heterogeneity.

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Abstract

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