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

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

doi:10.1101/2024.02.09.24302464

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

medRxiv [Preprint]. 2024 Feb 13:2024.02.09.24302464. doi: 10.1101/2024.02.09.24302464.

Authors

Daniel G Calame^{1

2

3}, Jovi Huixin Wong⁴, Puravi Panda⁴, Dat Tuan Nguyen⁴, Nancy C P Leong⁴, Riccardo Sangermano⁵, Sohil G Patankar⁵, Mohamed Abdel-Hamid⁶, Lama AlAbdi^{7

8}, Sylvia Safwat⁹, Kyle P Flannery¹⁰, Zain Dardas³, Jawid M Fatih³, Chaya Murali³, Varun Kannan¹, Timothy E Lotze¹, Isabella Herman^{1

2

3

11}, Farah Ammouri^{11

12}, Brianna Rezich¹³, Stephanie Efthymiou¹⁴, Shahryar Alavi¹⁴, David Murphy¹⁵, Zahra Firoozfar¹⁶, Mahya Ebrahimi Nasab^{17

18}, Amir Bahreini^{19

20}, Majid Ghasemi²¹, Nourelhoda A Haridy²², Hamid Reza Goldouzi²³, Fatemeh Eghbal²⁴, Ehsan Ghayoor Karimiani²⁵, Varunvenkat M Srinivasan²⁶, Vykuntaraju K Gowda²⁶, Haowei Du³, Shalini N Jhangiani²⁷, Zeynep Coban-Akdemir^{3

28}, Dana Marafi^{3

29}, Lance Rodan^{30

31}, Sedat Isikay³², Jill A Rosenfeld^{3

33}, Subhadra Ramanathan³⁴, Michael Staton³⁴, Kerby C Oberg³⁵, Robin D Clark³⁴, Catharina Wenman³⁶, Sam Loughlin³⁶, Ramy Saad³⁷, Tazeen Ashraf³⁷, Alison Male³⁷, Shereen Tadros³⁷, Reza Boostani³⁸, Ghada M H Abdel-Salam³⁹, Maha Zaki³⁹, Ebtesam Abdalla⁹, M Chiara Manzini¹⁰, Davut Pehlivan^{1

2

3}, Jennifer E Posey³, Richard A Gibbs^{3

27}, Henry Houlden¹⁴, Fowzan S Alkuraya^{8

40}, Kinga Bujakowska⁵, Reza Maroofian¹⁴, James R Lupski^{2

3

27

41}, Long Nam Nguyen^{4

42

43

44

45}

Affiliations

¹ Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
² Texas Children's Hospital, Houston, TX, USA.
³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁴ Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.
⁵ Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.
⁶ Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
⁷ Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia.
⁸ Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
⁹ Department of Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt.
¹⁰ Department of Neuroscience and Cell Biology, Rutgers-Robert Wood Johnson Medical School, Child Health Institute of New Jersey, NY, USA.
¹¹ Boys Town National Research Hospital, Boys Town, NE, USA.
¹² The University of Kansas Health System, Westwood, KS, USA.
¹³ Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, NE, USA.
¹⁴ Department of Neuromuscular diseases, UCL Institute of Neurology, WC1N 3BG, London, UK.
¹⁵ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, United Kingdom.
¹⁶ Palindrome, Isfahan, Iran.
¹⁷ Meybod Genetic Research Center, Yazd, Iran.
¹⁸ Yazd Welfare Organization, Yazd, Iran.
¹⁹ KaryoGen, Isfahan, Iran.
²⁰ Department of Human Genetics, University of Pittsburgh, PA, USA.
²¹ Department of Neurology, Isfahan University of Medical Sciences, Isfahan, Iran.
²² Department of Neurology, Faculty of Medicine, Assiut University, Assiut, Egypt.
²³ Department of Pediatrics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
²⁴ Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran.
²⁵ Molecular and Clinical Sciences Institute, St George's, University of London, Cranmer Terrace London, London, UK.
²⁶ Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India.
²⁷ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
²⁸ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
²⁹ Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait.
³⁰ Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.
³¹ Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.
³² Gaziantep Islam Science and Technology University, Medical Faculty, Department of Pediatric Neurology, Gaziantep, Turkey.
³³ Baylor Genetics Laboratories, Houston, TX, USA.
³⁴ Division of Genetics, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA, USA.
³⁵ Department of Pathology and Human Anatomy, Loma Linda University School of Medicine, Loma Linda, CA, USA.
³⁶ Rare & Inherited Disease Laboratory, NHS North Thames Genomic Laboratory Hub, Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3BH, UK.
³⁷ North East Thames Regional Genetic Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
³⁸ Department of Neurology, Mashhad University of Medical Sciences, Mashhad, Iran.
³⁹ Department of Clinical Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
⁴⁰ Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
⁴¹ Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
⁴² Immunology Program, Life Sciences Institute, National University of Singapore, Singapore 117456.
⁴³ Singapore Lipidomics Incubator (SLING), Life Sciences Institute, National University of Singapore, Singapore 117456.
⁴⁴ Cardiovascular Disease Research (CVD) Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545.
⁴⁵ Immunology Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456.

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.

Keywords: Diamond-Blackfan anemia; FLVCR1; choline; ethanolamine; multiple congenital anomalies; neurodegeneration; neurodevelopmental disorders.

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Abstract

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