Mfsd7b facilitates choline transport and missense mutations affect choline transport function

Ha, Hoa Thi Thuy; Sukumar, Viresh Krishnan; Chua, Jonathan Wei Bao; Nguyen, Dat T.; Nguyen, Toan Q.; Lim, Lina Hsiu Kim; Cazenave-Gassiot, Amaury; Nguyen, Long N.

doi:10.1007/s00018-023-05048-4

Cited by 9 publications

(13 citation statements)

References 24 publications

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“…Second, the cellular phenotype assessed by the choline transport assay must be distinguished from the organismal phenotypes characterized in humans with pathogenic FLVCR1 variation. Third, FLVCR1 was found to transport additional ligands like ethanolamine in both this study and previous studies 14 . While a reduction in both choline and ethanolamine transport was observed with most variants, some like p.S305R had a more severe impact on ethanolamine than choline transport.…”

Section: Textsupporting

confidence: 82%

“…To investigate the molecular consequence of FLVCR1 missense variants on gene function, we generated missense variants using site-directed mutagenesis of human FLVCR1 cDNA and examined each variant’s choline and ethanolamine transport activity ( Fig. 4 ) 14 .…”

Section: Textmentioning

confidence: 99%

“…HEK293 cells were then incubated with [ 3 H] choline or [ 14 C] ethanolamine, washed, and cellular radioactivity levels were measured. CHKA catalyzes choline phosphorylation into phosphocholine while ETNK1 catalyzes ethanolamine into phosphatidylethanolamine; their co-expression along with FLVCR1 greatly increases choline or ethanolamine import 14 . In addition to the FLVCR1 missense variants identified in this publication, we also examined p.Q124L and p.G219C, two FLVCR1 variants recently identified in an individual with HSAN 19,34 .…”

Section: Textmentioning

confidence: 99%

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Biallelic variation in the choline and ethanolamine transporterFLVCR1underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders

Calame,

Wong,

Panda

et al. 2024

Preprint

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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.

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Section: Textsupporting

confidence: 82%

Section: Textmentioning

confidence: 99%

Section: Textmentioning

confidence: 99%

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Biallelic variation in the choline and ethanolamine transporterFLVCR1underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders

Calame,

Wong,

Panda

et al. 2024

Preprint

Self Cite

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“…While this model aligns with the current findings, recent discoveries indicate the possibility of alternative explanations. Specifically, FLVCR1a has been shown to function as a choline importer, playing a crucial role in phosphatidylcholine production-the primary component of cell membranes [38][39][40]. Consequently, the positive influence of FLVCR1a on heme synthesis might not be directly orchestrated by heme control but rather indirectly through choline metabolism.…”

Section: Discussionmentioning

confidence: 99%

FLVCR1a Controls Cellular Cholesterol Levels through the Regulation of Heme Biosynthesis and Tricarboxylic Acid Cycle Flux in Endothelial Cells

Manco,

Ammirata,

Petrillo

et al. 2024

Biomolecules

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Feline leukemia virus C receptor 1a (FLVCR1a), initially identified as a retroviral receptor and localized on the plasma membrane, has emerged as a crucial regulator of heme homeostasis. Functioning as a positive regulator of δ-aminolevulinic acid synthase 1 (ALAS1), the rate-limiting enzyme in the heme biosynthetic pathway, FLVCR1a influences TCA cycle cataplerosis, thus impacting TCA flux and interconnected metabolic pathways. This study reveals an unexplored link between FLVCR1a, heme synthesis, and cholesterol production in endothelial cells. Using cellular models with manipulated FLVCR1a expression and inducible endothelial-specific Flvcr1a-null mice, we demonstrate that FLVCR1a-mediated control of heme synthesis regulates citrate availability for cholesterol synthesis, thereby influencing cellular cholesterol levels. Moreover, alterations in FLVCR1a expression affect membrane cholesterol content and fluidity, supporting a role for FLVCR1a in the intricate regulation of processes crucial for vascular development and endothelial function. Our results underscore FLVCR1a as a positive regulator of heme synthesis, emphasizing its integration with metabolic pathways involved in cellular energy metabolism. Furthermore, this study suggests that the dysregulation of heme metabolism may have implications for modulating lipid metabolism. We discuss these findings in the context of FLVCR1a’s potential heme-independent function as a choline importer, introducing additional complexity to the interplay between heme and lipid metabolism.

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“…Remarkably, the necessity for a comprehensive characterization of this transporter has become increasingly urgent in recent months, following the publication of new studies that have cast doubt on the existing literature. Indeed, emerging research [ 12 , 13 , 14 ] has raised queries regarding FLVCR1a's established role as a heme exporter and has put forth an alternative function as a choline importer, proposing a re-evaluation of prior findings. These studies have stimulated an ongoing debate, which remains unresolved as of the writing of this manuscript.…”

Section: Introductionmentioning

confidence: 99%

Unearthing FLVCR1a: tracing the path to a vital cellular transporter

Fiorito,

Tolosano

2024

Cell. Mol. Life Sci.

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The Feline Leukemia Virus Subgroup C Receptor 1a (FLVCR1a) is a member of the SLC49 Major Facilitator Superfamily of transporters. Initially recognized as the receptor for the retrovirus responsible of pure red cell aplasia in cats, nearly two decades since its discovery, FLVCR1a remains a puzzling transporter, with ongoing discussions regarding what it transports and how its expression is regulated. Nonetheless, despite this, the substantial body of evidence accumulated over the years has provided insights into several critical processes in which this transporter plays a complex role, and the health implications stemming from its malfunction. The present review intends to offer a comprehensive overview and a critical analysis of the existing literature on FLVCR1a, with the goal of emphasising the vital importance of this transporter for the organism and elucidating the interconnections among the various functions attributed to this transporter.

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Mfsd7b facilitates choline transport and missense mutations affect choline transport function

Cited by 9 publications

References 24 publications

Biallelic variation in the choline and ethanolamine transporterFLVCR1underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders

Biallelic variation in the choline and ethanolamine transporterFLVCR1underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders

FLVCR1a Controls Cellular Cholesterol Levels through the Regulation of Heme Biosynthesis and Tricarboxylic Acid Cycle Flux in Endothelial Cells

Unearthing FLVCR1a: tracing the path to a vital cellular transporter

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