Mutations in FLVCR1 Cause Posterior Column Ataxia and Retinitis Pigmentosa

Abstract

The study of inherited retinal diseases has advanced our knowledge of the cellular and molecular mechanisms involved in sensory neural signaling. Dysfunction of two specific sensory modalities, vision and proprioception, characterizes the phenotype of the rare, autosomal-recessive disorder posterior column ataxia and retinitis pigmentosa (PCARP). Using targeted DNA capture and high-throughput sequencing, we analyzed the entire 4.2 Mb candidate sequence on chromosome 1q32 to find the gene mutated in PCARP in a single family. Employing comprehensive bioinformatic analysis and filtering, we identified a single-nucleotide coding variant in the feline leukemia virus subgroup C cellular receptor 1 (FLVCR1), a gene encoding a heme-transporter protein. Sanger sequencing confirmed the FLVCR1 mutation in this family and identified different homozygous missense mutations located within the protein's transmembrane channel segment in two other unrelated families with PCARP. To determine whether the selective pathologic features of PCARP correlated with FLVCR1 expression, we examined wild-type mouse Flvcr1 mRNA levels in the posterior column of the spinal cord and the retina via quantitative real-time reverse-transcriptase PCR. The Flvcr1 mRNA levels were most abundant in the retina, followed by the posterior column of the spinal cord and other brain regions. These results suggest that aberrant FLVCR1 causes a selective degeneration of a subpopulation of neurons in the retina and the posterior columns of the spinal cord via dysregulation of heme or iron homeostasis. This finding broadens the molecular basis of sensory neural signaling to include common mechanisms that involve proprioception and vision.

Mitochondrial heme: an exit strategy at last

“…FLVCR1 mutations in DBA patients have not been found as of yet (19); however, if they were to exist, one would predict that they would occur in the FLVCR1b isoform. Interestingly, missense mutations in FLVCR1 have recently been described in patients with the rare autosomal recessive disease posterior column ataxia and retinitis pigmentosa (PCARP) (20,21). Three of the four reported disease-associated FLVCR1 variants, all of which are present in the homozygous state in PCARP patients, occur in exon 1 of the gene -the part of the gene that is omitted in the FLVCR1b transcript and protein.…”

Deep-sequencing reveals clonal evolution patterns and mutation events associated with relapse in B-cell lymphomas

“…We achieved 65 ± 17X sequencing depth on average and at least 20X depth on 81.7 ± 7.8% of the region targeted. We performed single nucleotide variants (SNVs) calling using a previously published procedure [14][15][16]. We directly compared each relapse sample to its matched diagnosis tumor to identify gained or lost coding region nonsynonynmous SNVs at relapse (SNVs within copy number alteration (CNA) regions were excluded; Figure 2A; Additional file 4).…”

“…Duplicated paired reads were filtered and variant detection was performed as previously described [14][15][16]. Novel coding region SNVs (not present in SNP132) were further filtered according to sequencing depth (≥20X) and variant percentage (≥25%).…”

Coupling Heme and Iron MetabolismviaFerritin H Chain

“…To see this illustration in color, the reader is referred to the web version of this article at www .liebertpub.com/ars mitochondrial FLVCR1 expression, given that specific deletion of the Flvcr1a gene variant is dispensable for erythropoiesis, although necessary to prevent edema and hemorrhage (35). FLVCR1 mutations in humans are associated with the development of posterior column ataxia and retinitis pigmentosa (136), whereas FLVCR2 mutations have been associated to proliferative brain vasculopathy, such as observed in the Fowler syndrome (47). Conversely, mutations in ABCG2 and ABCB6 do not impair erythroid differentiation, suggesting a redundant role for these transporters in erythropoiesis (75,144,189).…”