Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency

Brain : a Journal of Neurology
Marcel GrappRobert Steinfeld

Abstract

Cerebral folate transport deficiency is an inherited brain-specific folate transport defect that is caused by mutations in the folate receptor 1 gene coding for folate receptor alpha (FRα). This genetic defect gives rise to a progressive neurological disorder with late infantile onset. We screened 72 children with low 5-methyltetrahydrofolate concentrations in the cerebrospinal fluid and neurological symptoms that developed after infancy. We identified nucleotide alterations in the folate receptor 1 gene in 10 individuals who shared developmental regression, ataxia, profound cerebral hypomyelination and cerebellar atrophy. We found four novel pathogenic alleles, one splice mutation and three missense mutations. Heterologous expression of the missense mutations, including previously described mutants, revealed minor decrease in protein expression but loss of cell surface localization, mistargeting to intracellular compartments and thus absence of cellular binding of folic acid. These results explain the functional loss of folate receptor alpha for all detected folate receptor 1 mutations. Three individuals presenting a milder clinical phenotype revealed very similar biochemical and brain imaging data but partially shared pathoge...Continue Reading

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Citations

Jul 6, 2013·Nature Communications·Marcel GrappRobert Steinfeld
Aug 29, 2013·Epilepsy Research and Treatment·Satish AgadiZulfi Haneef
Mar 20, 2013·Molecular Aspects of Medicine·Rongbao Zhao, I David Goldman
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