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

Area of Science:

• Genetics
• Neuroscience
• Biochemistry

Background:

• Cerebral folate transport deficiency (CFTD) is an inherited neurological disorder.
• It stems from mutations in the folate receptor 1 gene, affecting folate receptor alpha (FRα).
• CFTD presents as a progressive neurological disorder with late infantile onset.

Purpose of the Study:

• To investigate the genetic basis and functional consequences of folate receptor 1 mutations in children with CFTD.
• To identify novel mutations and understand their impact on FRα function and clinical presentation.

Main Methods:

• Screening of 72 children with low cerebrospinal fluid 5-methyltetrahydrofolate and neurological symptoms.
• Genetic analysis of the folate receptor 1 gene to identify nucleotide alterations.
• Heterologous expression of identified missense mutations to assess FRα protein function and localization.

Main Results:

• Identified folate receptor 1 gene alterations in 10 individuals with developmental regression, ataxia, hypomyelination, and cerebellar atrophy.
• Discovered four novel pathogenic alleles: one splice and three missense mutations.
• Missense mutations resulted in reduced protein expression, loss of cell surface localization, and impaired folic acid binding, explaining functional loss of FRα.

Conclusions:

• The identified folate receptor 1 mutations lead to functional loss of FRα, causing cerebral folate transport deficiency.
• Clinical severity in CFTD does not strictly correlate with residual FRα function.
• Additional genetic or environmental factors likely contribute to the variable clinical phenotypes observed in CFTD.