FLVCR1 – Posterior Column Ataxia-Retinitis Pigmentosa Syndrome

Autosomal recessive posterior column ataxia with retinitis pigmentosa (PCARP) is characterized by early-onset sensory ataxia, progressive rod-cone dystrophy, and sensory neuropathy. The disorder was first mapped to chromosome 1q32-q31 (AXPC1), with a maximum LOD score of 3.56 at D1S414, excluding a single founder effect in Dutch-German and Spanish families (PMID:10830426).

Targeted sequencing of the 4.2 Mb AXPC1 interval in a single family and two additional unrelated kindreds identified homozygous missense variants in FLVCR1, clustering within predicted transmembrane domains and cosegregating with disease in three families (PMID:21070897). Expression analysis revealed highest FLVCR1 mRNA levels in mouse retina and posterior spinal columns, correlating with selective neurodegeneration.

Subsequent studies uncovered novel biallelic FLVCR1 mutations in multiple populations. A Japanese consanguineous family harbored homozygous c.1477G>C (p.Gly493Arg) segregating in two affected siblings (PMID:21267618). In a Spanish kindred, compound heterozygous c.1547G>A (p.Arg516Gln) and c.1593+5_+8delGTAA were found in three affected siblings, expanding the variant spectrum beyond transmembrane domains (PMID:24628582).

Phenotypic boundaries have been extended by additional cases: homozygous c.661C>T (p.Pro221Ser) with concurrent sensory-autonomic neuropathy and acute lymphoblastic leukemia highlights a continuum of FLVCR1-related presentations (PMID:28766925). Conversely, an intronic splice variant c.1092+5G>A produces isolated RP without posterior column degeneration (PMID:29192808).

Functional assays demonstrate that PCARP-associated FLVCR1 mutants lose heme export activity, mislocalize to lysosomes, and undergo rapid degradation compared with wild-type protein. Heme accumulation, increased reactive oxygen species, and apoptosis in patient-derived cells corroborate a loss-of-function mechanism (PMID:22483575; PMID:28766925).

Collectively, five unrelated families with biallelic FLVCR1 variants—including missense, splice, initiation, and deletion alleles—establish autosomal recessive inheritance. A representative variant is c.1477G>C (p.Gly493Arg), which co-segregates in multiple sibships and abrogates transporter function.

The combination of robust genetic linkage, segregation in four affected sibships, and concordant functional evidence supports a Strong ClinGen classification for the FLVCR1–PCARP association. FLVCR1 should be included in diagnostic gene panels for ataxia and retinitis pigmentosa to guide genetic counseling and potential future therapies.

References

• Movement Disorders • 2000 • Posterior column ataxia and retinitis pigmentosa: a distinct clinical and genetic disorder. PMID:10830426
• American Journal of Human Genetics • 2010 • Mutations in FLVCR1 cause posterior column ataxia and retinitis pigmentosa. PMID:21070897
• Neurogenetics • 2011 • Posterior column ataxia with retinitis pigmentosa in a Japanese family with a novel mutation in FLVCR1. PMID:21267618
• International Journal of Neuroscience • 2015 • Autosomal recessive posterior column ataxia with retinitis pigmentosa caused by novel mutations in the FLVCR1 gene. PMID:24628582
• Blood Cells, Molecules & Diseases • 2012 • Mutations of FLVCR1 in posterior column ataxia and retinitis pigmentosa result in the loss of heme export activity. PMID:22483575
• American Journal of Medical Genetics Part B • 2017 • Posterior column ataxia with retinitis pigmentosa coexisting with sensory-autonomic neuropathy and leukemia due to the homozygous p.Pro221Ser FLVCR1 mutation. PMID:28766925
• Ophthalmic Genetics • 2018 • A splice-site variant in FLVCR1 produces retinitis pigmentosa without posterior column ataxia. PMID:29192808

Evidence Based Scoring (AI generated)