• Open Access

WDR19: An ancient, retrograde, intraflagellar ciliary protein is mutated in autosomal recessive retinitis pigmentosa and in Senior-Loken syndrome

Authors

  • R G Coussa,

    1. Department of Paediatric Surgery
    2. Department of Radiology
    3. Department of Ophthalmology
    4. Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada
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  • E A Otto,

    1. Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA
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  • H-Y Gee,

    1. Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
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  • P Arthurs,

    1. Department of Paediatric Surgery
    2. Department of Radiology
    3. Department of Ophthalmology
    4. Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada
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  • H Ren,

    1. Department of Paediatric Surgery
    2. Department of Radiology
    3. Department of Ophthalmology
    4. Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada
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  • I Lopez,

    1. Department of Paediatric Surgery
    2. Department of Radiology
    3. Department of Ophthalmology
    4. Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada
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  • V Keser,

    1. Department of Paediatric Surgery
    2. Department of Radiology
    3. Department of Ophthalmology
    4. Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada
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  • Q Fu,

    1. Department of Paediatric Surgery
    2. Department of Radiology
    3. Department of Ophthalmology
    4. Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada
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  • R Faingold,

    1. Department of Paediatric Surgery
    2. Department of Radiology
    3. Department of Ophthalmology
    4. Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada
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  • A Khan,

    1. Department of Paediatric Surgery
    2. Department of Radiology
    3. Department of Ophthalmology
    4. Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada
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  • J Schwartzentruber,

    1. Department of Human Genetics, McGill University, Montreal, Quebec, Canada
    2. McGill University and Genome Quebec Innovation Center, Montreal, Quebec, Canada
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  • J Majewski,

    1. Department of Human Genetics, McGill University, Montreal, Quebec, Canada
    2. McGill University and Genome Quebec Innovation Center, Montreal, Quebec, Canada
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  • F Hildebrandt,

    1. Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
    2. Howard Hughes Medical Institute, Chevy Chase, MD, USA
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  • R K Koenekoop

    Corresponding author
    1. Department of Radiology
    2. Department of Ophthalmology
    3. Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada
    • Department of Paediatric Surgery
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  • We have no conflict of interest to disclose in the work presented in this article.

Corresponding author: Robert K. Koenekoop, MD, PhD, Department of Ophthalmology, McGill University Health Centre, Room D-168, 2300 Tupper, Montreal, Quebec H3H 1P3, Canada.

Tel.: +1 514 412 4400x22891/22530;

fax: +1 514 412 4443;

e-mail: robkoenekoop@hotmail.com

Abstract

Autosomal recessive retinitis pigmentosa (arRP) is a clinically and genetically heterogeneous retinal disease that causes blindness. Our purpose was to identify the causal gene, describe the phenotype and delineate the mutation spectrum in a consanguineous Quebec arRP family. We performed Arrayed Primer Extension (APEX) technology to exclude ∼500 arRP mutations in ∼20 genes. Homozygosity mapping [single nucleotide polymorphism (SNP) genotyping] identified 10 novel significant homozygous regions. We performed next generation sequencing and whole exome capture. Sanger sequencing provided cosegregation. We screened another 150 retinitis pigmentosa (RP) and 200 patients with Senior-Løken Syndrome (SLS). We identified a novel missense mutation in WDR19, c.2129T>C which lead to a p.Leu710Ser. We found the same mutation in a second Quebec arRP family. Interestingly, two of seven affected members of the original family developed ‘sub-clinical’ renal cysts. We hypothesized that more severe WDR19 mutations may lead to severe ciliopathies and found seven WDR19 mutations in five SLS families. We identified a new gene for both arRP and SLS. WDR19 is a ciliary protein associated with the intraflagellar transport machinery. We are currently investigating the full extent of the mutation spectrum. Our findings are crucial in expanding the understanding of childhood blindness and identifying new genes.

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