Biallelic variation in the choline and ethanolamine transporter<i>FLVCR1</i>underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders
Abstract 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..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 15. Feb. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2024.02.09.24302464 |
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| PPN (Katalog-ID): |
XBI042491282 |
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| 245 | 1 | 0 | |a 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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| 520 | |a Abstract 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. | ||
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