Biallelic variation in the choline and ethanolamine transporterFLVCR1underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders
Authors: Calame Daniel G. , Wong Jovi Huixin , Panda Puravi , Nguyen Dat Tuan , Leong Nancy C.P. , Sangermano Riccardo , Patankar Sohil G. , Abdel-Hamid Mohamed , AlAbdi Lama , Safwat Sylvia , Flannery Kyle P. , Dardas Zain , Fatih Jawid M. , Murali Chaya , Kannan Varun , Lotze Timothy E. , Herman Isabella , Ammouri Farah , Rezich Brianna , Efthymiou Stephanie , Alavi Shahryar , Murphy David , Firoozfar Zahra , Nasab Mahya Ebrahimi , Bahreini Amir , Ghasemi Majid , Haridy Nourelhoda A. , Goldouzi Hamid Reza , Eghbal Fatemeh , Karimiani Ehsan Ghayoor , Srinivasan Varunvenkat M. , Gowda Vykuntaraju K. , Du Haowei , Jhangiani Shalini N. , Coban-Akdemir Zeynep , Marafi Dana , Rodan Lance , Isikay Sedat , Rosenfeld Jill A. , Ramanathan Subhadra , Staton Michael , Oberg Kerby C. , Clark Robin D. , Wenman Catharina , Loughlin Sam , Saad Ramy , Ashraf Tazeen , Male Alison , Tadros Shereen , Boostani Reza , Abdel-Salam Ghada M.H. , Zaki Maha , Abdalla Ebtesam , Chiara Manzini M. , Pehlivan Davut , Posey Jennifer E. , Gibbs Richard A. , Houlden Henry , Alkuraya Fowzan S. , Bujakowska Kinga , Maroofian Reza , Lupski James R. , Nguyen Long Nam 
Published: February 2024

FLVCR1encodes 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. WhileFlvcr1knockout mice diein uterowith skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia, rare biallelic pathogenicFLVCR1variants 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)FLVCR1variant alleles. We characterize an expansiveFLVCR1phenotypic 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 withFlvcr1knockout mice and Diamond-Blackfan anemia including macrocytic anemia and congenital skeletal malformations. PathogenicFLVCR1missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-typeFLVCR1with 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.