Mutations in FLVCR1 cause posterior column ataxia and retinitis pigmentosa

Anjali M. Rajadhyaksha; Olivier Elemento; Erik G. Puffenberger; Kathryn C. Schierberl; Jenny Z. Xiang; Maria L. Putorti; José Berciano; Chantal Poulin; Bernard Brais; Michel Michaelides; Richard G. Weleber; Joseph J. Higgins

doi:10.1016/j.ajhg.2010.10.013

Mutations in FLVCR1 cause posterior column ataxia and retinitis pigmentosa

Anjali M. Rajadhyaksha
, Olivier Elemento
, Erik G. Puffenberger
, Kathryn C. Schierberl
, Jenny Z. Xiang
, Maria L. Putorti
, José Berciano
, Chantal Poulin
, Bernard Brais
, Michel Michaelides
, Richard G. Weleber
, Joseph J. Higgins

Ophthalmology

Research output: Contribution to journal › Article › peer-review

96 Scopus citations

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.

Original language	English (US)
Pages (from-to)	643-654
Number of pages	12
Journal	American Journal of Human Genetics
Volume	87
Issue number	5
DOIs	https://doi.org/10.1016/j.ajhg.2010.10.013
State	Published - Nov 12 2010

Funding

We thank the families for their participation in this study. This research was supported by intramural funding from the National Institute of Neurological Disorders and Stroke (NINDS), of the US National Institutes of Health, and the New York State Department of Health (to J.J.H.) and by funds from The Hartwell Foundation (to A.M.R. and J.J.H.). The Association de la Neuropathie Sensorielle et Autonomique Héréditaire de Type 2 supported the recruitment and genetic mapping of the French Canadian family by C.P. and B.B. The Foundation Fighting Blindness (Columbia, MD, USA) and an unrestricted grant from Research to Prevent Blindness (New York, NY, USA) supported R.G.W. in the evaluation of the Western European families. M.M. was supported by grants from Moorfields Special Trustees and the National Institute for Health Research UK to the Biomedical Research Centre for Ophthalmology, based at Moorfields Eye Hospital NHS Foundation Trust and the University College London Institute of Ophthalmology, UK. We thank B.E. Kosofsky, Chief, Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medical College, New York, New York, USA, for securing funding for resequencing; D.H. Morton and the staff at the Clinic for Special Children in Strasburg, PA, USA for financially supporting the sequencing of candidate genes in the American family; S. Ra and A.L. Tal from the Laboratory of Molecular and Developmental Neurobiology, Weill Cornell Medical College, New York, NY, USA for their technical assistance; and N.B. Stover from the Oregon Retinal Degeneration Center, Casey Eye Institute, Portland, OR, USA, S.J. Hayflick and P. Hogarth from the Departments of Neurology and Medical & Molecular Genetics, and S.K. Westaway from the Departments of Neurology and Cardiology, Oregon Health & Science University, Portland, OR, USA for characterizing the two Western European families with a PCARP-like phenotype.

Funders
Moorfields Eye Hospital Special Trustees
National Institute for Health Research Doctoral Research
Author National Institutes of Health National Institutes of Health National Institutes of Health National Institutes of Health The Bev Hartig Huntington's Disease Foundation National Institutes of Health
National Institute of Neurological Disorders and Stroke
New York State Department of Health
Hartwell Foundation
UCL Institute of Ophthalmology, University College London
Moorfields Eye Hospital NHS Foundation Trust

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1016/j.ajhg.2010.10.013

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Rajadhyaksha, A. M., Elemento, O., Puffenberger, E. G., Schierberl, K. C., Xiang, J. Z., Putorti, M. L., Berciano, J., Poulin, C., Brais, B., Michaelides, M., Weleber, R. G., & Higgins, J. J. (2010). Mutations in FLVCR1 cause posterior column ataxia and retinitis pigmentosa. American Journal of Human Genetics, 87(5), 643-654. https://doi.org/10.1016/j.ajhg.2010.10.013

@article{609fb94c068c404dad140e83c56df45c,

title = "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.",

author = "Rajadhyaksha, \{Anjali M.\} and Olivier Elemento and Puffenberger, \{Erik G.\} and Schierberl, \{Kathryn C.\} and Xiang, \{Jenny Z.\} and Putorti, \{Maria L.\} and Jos{\'e} Berciano and Chantal Poulin and Bernard Brais and Michel Michaelides and Weleber, \{Richard G.\} and Higgins, \{Joseph J.\}",

note = "Funding Information: We thank the families for their participation in this study. This research was supported by intramural funding from the National Institute of Neurological Disorders and Stroke (NINDS), of the US National Institutes of Health, and the New York State Department of Health (to J.J.H.) and by funds from The Hartwell Foundation (to A.M.R. and J.J.H.). The Association de la Neuropathie Sensorielle et Autonomique H{\'e}r{\'e}ditaire de Type 2 supported the recruitment and genetic mapping of the French Canadian family by C.P. and B.B. The Foundation Fighting Blindness (Columbia, MD, USA) and an unrestricted grant from Research to Prevent Blindness (New York, NY, USA) supported R.G.W. in the evaluation of the Western European families. M.M. was supported by grants from Moorfields Special Trustees and the National Institute for Health Research UK to the Biomedical Research Centre for Ophthalmology, based at Moorfields Eye Hospital NHS Foundation Trust and the University College London Institute of Ophthalmology, UK. We thank B.E. Kosofsky, Chief, Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medical College, New York, New York, USA, for securing funding for resequencing; D.H. Morton and the staff at the Clinic for Special Children in Strasburg, PA, USA for financially supporting the sequencing of candidate genes in the American family; S. Ra and A.L. Tal from the Laboratory of Molecular and Developmental Neurobiology, Weill Cornell Medical College, New York, NY, USA for their technical assistance; and N.B. Stover from the Oregon Retinal Degeneration Center, Casey Eye Institute, Portland, OR, USA, S.J. Hayflick and P. Hogarth from the Departments of Neurology and Medical \& Molecular Genetics, and S.K. Westaway from the Departments of Neurology and Cardiology, Oregon Health \& Science University, Portland, OR, USA for characterizing the two Western European families with a PCARP-like phenotype. ",

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doi = "10.1016/j.ajhg.2010.10.013",

language = "English (US)",

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AU - Rajadhyaksha, Anjali M.

AU - Elemento, Olivier

AU - Puffenberger, Erik G.

AU - Schierberl, Kathryn C.

AU - Xiang, Jenny Z.

AU - Putorti, Maria L.

AU - Berciano, José

AU - Poulin, Chantal

AU - Brais, Bernard

AU - Michaelides, Michel

AU - Weleber, Richard G.

AU - Higgins, Joseph J.

N1 - Funding Information: We thank the families for their participation in this study. This research was supported by intramural funding from the National Institute of Neurological Disorders and Stroke (NINDS), of the US National Institutes of Health, and the New York State Department of Health (to J.J.H.) and by funds from The Hartwell Foundation (to A.M.R. and J.J.H.). The Association de la Neuropathie Sensorielle et Autonomique Héréditaire de Type 2 supported the recruitment and genetic mapping of the French Canadian family by C.P. and B.B. The Foundation Fighting Blindness (Columbia, MD, USA) and an unrestricted grant from Research to Prevent Blindness (New York, NY, USA) supported R.G.W. in the evaluation of the Western European families. M.M. was supported by grants from Moorfields Special Trustees and the National Institute for Health Research UK to the Biomedical Research Centre for Ophthalmology, based at Moorfields Eye Hospital NHS Foundation Trust and the University College London Institute of Ophthalmology, UK. We thank B.E. Kosofsky, Chief, Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medical College, New York, New York, USA, for securing funding for resequencing; D.H. Morton and the staff at the Clinic for Special Children in Strasburg, PA, USA for financially supporting the sequencing of candidate genes in the American family; S. Ra and A.L. Tal from the Laboratory of Molecular and Developmental Neurobiology, Weill Cornell Medical College, New York, NY, USA for their technical assistance; and N.B. Stover from the Oregon Retinal Degeneration Center, Casey Eye Institute, Portland, OR, USA, S.J. Hayflick and P. Hogarth from the Departments of Neurology and Medical & Molecular Genetics, and S.K. Westaway from the Departments of Neurology and Cardiology, Oregon Health & Science University, Portland, OR, USA for characterizing the two Western European families with a PCARP-like phenotype.

PY - 2010/11/12

Y1 - 2010/11/12

N2 - 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.

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Mutations in FLVCR1 cause posterior column ataxia and retinitis pigmentosa

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