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Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders.

ABSTRACT: FLVCR1 encodes Feline leukemia virus subgroup C receptor 1 (FLVCR1), a solute carrier (SLC) transporter within the Major Facilitator Superfamily. FLVCR1 is a widely expressed transmembrane protein with plasma membrane and mitochondrial isoforms implicated in heme, choline, and ethanolamine transport. While Flvcr1 knockout mice die in utero with skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia, rare biallelic pathogenic FLVCR1 variants are linked to childhood or adult-onset neurodegeneration of the retina, spinal cord, and peripheral nervous system. We ascertained from research and clinical exome sequencing 27 individuals from 20 unrelated families with biallelic ultra-rare missense and predicted loss-of-function (pLoF) FLVCR1 variant alleles. We characterize an expansive FLVCR1 phenotypic spectrum ranging from adult-onset retinitis pigmentosa to severe developmental disorders with microcephaly, reduced brain volume, epilepsy, spasticity, and premature death. The most severely affected individuals, including three individuals with homozygous pLoF variants, share traits with Flvcr1 knockout mice and Diamond-Blackfan anemia including macrocytic anemia and congenital skeletal malformations. Pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1 with minimal impact on FLVCR1 stability or subcellular localization. Several variants disrupt splicing in a mini-gene assay which may contribute to genotype-phenotype correlations. Taken together, these data support an allele-specific gene dosage model in which phenotypic severity reflects residual FLVCR1 activity. This study expands our understanding of Mendelian disorders of choline and ethanolamine transport and demonstrates the importance of choline and ethanolamine in neurodevelopment and neuronal homeostasis.

SUBMITTER: Calame DG

PROVIDER: S-EPMC10888986 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders.

Calame Daniel G DG Wong Jovi Huixin JH Panda Puravi P Nguyen Dat Tuan DT Leong Nancy C P NCP Sangermano Riccardo R Patankar Sohil G SG Abdel-Hamid Mohamed M AlAbdi Lama L Safwat Sylvia S Flannery Kyle P KP Dardas Zain Z Fatih Jawid M JM Murali Chaya C Kannan Varun V Lotze Timothy E TE Herman Isabella I Ammouri Farah F Rezich Brianna B Efthymiou Stephanie S Alavi Shahryar S Murphy David D Firoozfar Zahra Z Nasab Mahya Ebrahimi ME Bahreini Amir A Ghasemi Majid M Haridy Nourelhoda A NA Goldouzi Hamid Reza HR Eghbal Fatemeh F Karimiani Ehsan Ghayoor EG Srinivasan Varunvenkat M VM Gowda Vykuntaraju K VK Du Haowei H Jhangiani Shalini N SN Coban-Akdemir Zeynep Z Marafi Dana D Rodan Lance L Isikay Sedat S Rosenfeld Jill A JA Ramanathan Subhadra S Staton Michael M Kerby C Oberg Clark Robin D RD Wenman Catharina C Loughlin Sam S Saad Ramy R Ashraf Tazeen T Male Alison A Tadros Shereen S Boostani Reza R Abdel-Salam Ghada M H GMH Zaki Maha M Abdalla Ebtesam E Manzini M Chiara MC Pehlivan Davut D Posey Jennifer E JE Gibbs Richard A RA Houlden Henry H Alkuraya Fowzan S FS Bujakowska Kinga K Maroofian Reza R Lupski James R JR Nguyen Long Nam LN

medRxiv : the preprint server for health sciences 20240213

FLVCR1 encodes Feline leukemia virus subgroup C receptor 1 (FLVCR1), a solute carrier (SLC) transporter within the Major Facilitator Superfamily. FLVCR1 is a widely expressed transmembrane protein with plasma membrane and mitochondrial isoforms implicated in heme, choline, and ethanolamine transport. While Flvcr1 knockout mice die in utero with skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia, rare biallelic pathogenic FLVCR1 ...[more]

PMID: 38405817

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Project description:In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death domain protein, regulates various cellular functions, such as vesicle trafficking, activity of the Rab3 and Rab27 small GTPases, tumour necrosis factor-α (TNF-α)-induced signalling and prevention of cell death. Through national collaboration and GeneMatcher, we collected 23 patients with 21 different pathogenic MADD variants identified by next-generation sequencing. We clinically evaluated the series of patients and categorized the phenotypes in two groups. Group 1 consists of 14 patients with severe developmental delay, endo- and exocrine dysfunction, impairment of the sensory and autonomic nervous system, and haematological anomalies. The clinical course during the first years of life can be potentially fatal. The nine patients in Group 2 have a predominant neurological phenotype comprising mild-to-severe developmental delay, hypotonia, speech impairment, and seizures. Analysis of mRNA revealed multiple aberrant MADD transcripts in two patient-derived fibroblast cell lines. Relative quantification of MADD mRNA and protein in fibroblasts of five affected individuals showed a drastic reduction or loss of MADD. We conducted functional tests to determine the impact of the variants on different pathways. Treatment of patient-derived fibroblasts with TNF-α resulted in reduced phosphorylation of the extracellular signal-regulated kinases 1 and 2, enhanced activation of the pro-apoptotic enzymes caspase-3 and -7 and increased apoptosis compared to control cells. We analysed internalization of epidermal growth factor in patient cells and identified a defect in endocytosis of epidermal growth factor. We conclude that MADD deficiency underlies multiple cellular defects that can be attributed to alterations of TNF-α-dependent signalling pathways and defects in vesicular trafficking. Our data highlight the multifaceted role of MADD as a signalling molecule in different organs and reveal its physiological role in regulating the function of the sensory and autonomic nervous system and endo- and exocrine glands.

Dataset Information

Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders.

Publications

Biallelic variation in the choline and ethanolamine transporter <i>FLVCR1</i> underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders.

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