Title | Biallelic variation in the choline and ethanolamine transporter underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders. |
Publication Type | Journal Article |
Year of Publication | 2024 |
Authors | Calame, DG, Wong, JHuixin, Panda, P, Nguyen, DTuan, Leong, NCP, Sangermano, R, Patankar, SG, Abdel-Hamid, M, Alabdi, L, Safwat, S, Flannery, KP, Dardas, Z, Fatih, JM, Murali, C, Kannan, V, Lotze, TE, Herman, I, Ammouri, F, Rezich, B, Efthymiou, S, Alavi, S, Murphy, D, Firoozfar, Z, Nasab, MEbrahimi, Bahreini, A, Ghasemi, M, Haridy, NA, Goldouzi, HReza, Eghbal, F, Karimiani, EGhayoor, Srinivasan, VM, Gowda, VK, Du, H, Jhangiani, SN, Coban-Akdemir, Z, Marafi, D, Rodan, L, Isikay, S, Rosenfeld, JA, Ramanathan, S, Staton, M, Clark, RD, Wenman, C, Loughlin, S, Saad, R, Ashraf, T, Male, A, Tadros, S, Boostani, R, Abdel-Salam, GMH, Zaki, M, Abdalla, E, M Manzini, C, Pehlivan, D, Posey, JE, Gibbs, RA, Houlden, H, Alkuraya, FS, Bujakowska, K, Maroofian, R, Lupski, JR, Nguyen, LNam |
Journal | medRxiv |
Date Published | 2024 Feb 13 |
Abstract | 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 knockout mice die with skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia, rare biallelic pathogenic 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) variant alleles. We characterize an expansive 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 knockout mice and Diamond-Blackfan anemia including macrocytic anemia and congenital skeletal malformations. Pathogenic missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type 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. |
DOI | 10.1101/2024.02.09.24302464 |
Alternate Journal | medRxiv |
PubMed ID | 38405817 |
PubMed Central ID | PMC10888986 |
Grant List | T32 GM007526 / GM / NIGMS NIH HHS / United States U24 HG011746 / HG / NHGRI NIH HHS / United States K23 NS125126 / NS / NINDS NIH HHS / United States R35 NS105078 / NS / NINDS NIH HHS / United States P30 EY014104 / EY / NEI NIH HHS / United States U01 HG011758 / HG / NHGRI NIH HHS / United States UM1 HG006542 / HG / NHGRI NIH HHS / United States U54 HG003273 / HG / NHGRI NIH HHS / United States |