A role for OCRL in glomerular function and disease

Rebecca Preston, Richard W. Naylor, Graham Stewart, Agnieszka Bierzynska, Moin A. Saleem, Martin Lowe, Rachel Lennon

    Research output: Contribution to journalArticle

    1 Citation (Scopus)
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    Abstract

    Background: Lowe syndrome and Dent-2 disease are caused by mutations in the OCRL gene, which encodes for an inositol 5-phosphatase. The renal phenotype associated with OCRL mutations typically comprises a selective proximal tubulopathy, which can manifest as Fanconi syndrome in the most extreme cases.

    Methods: Here, we report a 12-year-old male with nephrotic-range proteinuria and focal segmental glomerulosclerosis on renal biopsy. As a glomerular pathology was suspected, extensive investigation of tubular function was not performed.

    Results: Surprisingly, whole exome sequencing identified a genetic variant in OCRL (c1467-2A>G) that introduced a novel splice mutation leading to skipping of exon 15. In situ hybridisation of adult human kidney tissue and zebrafish larvae showed OCRL expression in the glomerulus, supporting a role for OCRL in glomerular function. In cultured podocytes, we found that OCRL associated with the linker protein IPIP27A and CD2AP, a protein that is important for maintenance of the podocyte slit diaphragm.

    Conclusion: Taken together, this work suggests a previously under-appreciated role for OCRL in glomerular function and highlights the importance of investigating tubular function in patients with persistent proteinuria.

    Original languageEnglish
    Number of pages8
    JournalPediatric Nephrology
    Early online date6 Dec 2019
    DOIs
    Publication statusE-pub ahead of print - 6 Dec 2019

    Fingerprint

    Podocytes
    Kidney
    Proteinuria
    Mutation
    Oculocerebrorenal Syndrome
    Fanconi Syndrome
    Exome
    Focal Segmental Glomerulosclerosis
    Zebrafish
    Diaphragm
    In Situ Hybridization
    Larva
    Exons
    Proteins
    Maintenance
    Pathology
    Phenotype
    Biopsy
    Genes
    1,7,9,11-tetrahydroxy-3-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo(a)tetracene-2-carboxylic acid

    Keywords

    • FSGS
    • Glomerular disease
    • Lowe syndrome
    • OCRL
    • Podocyte
    • Proteinuria

    Cite this

    Preston, R., Naylor, R. W., Stewart, G., Bierzynska, A., Saleem, M. A., Lowe, M., & Lennon, R. (2019). A role for OCRL in glomerular function and disease. Pediatric Nephrology. https://doi.org/10.1007/s00467-019-04317-4
    Preston, Rebecca ; Naylor, Richard W. ; Stewart, Graham ; Bierzynska, Agnieszka ; Saleem, Moin A. ; Lowe, Martin ; Lennon, Rachel. / A role for OCRL in glomerular function and disease. In: Pediatric Nephrology. 2019.
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    title = "A role for OCRL in glomerular function and disease",
    abstract = "Background: Lowe syndrome and Dent-2 disease are caused by mutations in the OCRL gene, which encodes for an inositol 5-phosphatase. The renal phenotype associated with OCRL mutations typically comprises a selective proximal tubulopathy, which can manifest as Fanconi syndrome in the most extreme cases.Methods: Here, we report a 12-year-old male with nephrotic-range proteinuria and focal segmental glomerulosclerosis on renal biopsy. As a glomerular pathology was suspected, extensive investigation of tubular function was not performed.Results: Surprisingly, whole exome sequencing identified a genetic variant in OCRL (c1467-2A>G) that introduced a novel splice mutation leading to skipping of exon 15. In situ hybridisation of adult human kidney tissue and zebrafish larvae showed OCRL expression in the glomerulus, supporting a role for OCRL in glomerular function. In cultured podocytes, we found that OCRL associated with the linker protein IPIP27A and CD2AP, a protein that is important for maintenance of the podocyte slit diaphragm.Conclusion: Taken together, this work suggests a previously under-appreciated role for OCRL in glomerular function and highlights the importance of investigating tubular function in patients with persistent proteinuria.",
    keywords = "FSGS, Glomerular disease, Lowe syndrome, OCRL, Podocyte, Proteinuria",
    author = "Rebecca Preston and Naylor, {Richard W.} and Graham Stewart and Agnieszka Bierzynska and Saleem, {Moin A.} and Martin Lowe and Rachel Lennon",
    note = "Funding for this research was provided by: Wellcome Trust (202860/Z/16/Z) National Institute for Health Research Lowe Syndrome Trust (ML/MU/2012)",
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    Preston, R, Naylor, RW, Stewart, G, Bierzynska, A, Saleem, MA, Lowe, M & Lennon, R 2019, 'A role for OCRL in glomerular function and disease', Pediatric Nephrology. https://doi.org/10.1007/s00467-019-04317-4

    A role for OCRL in glomerular function and disease. / Preston, Rebecca; Naylor, Richard W.; Stewart, Graham; Bierzynska, Agnieszka; Saleem, Moin A.; Lowe, Martin; Lennon, Rachel.

    In: Pediatric Nephrology, 06.12.2019.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - A role for OCRL in glomerular function and disease

    AU - Preston, Rebecca

    AU - Naylor, Richard W.

    AU - Stewart, Graham

    AU - Bierzynska, Agnieszka

    AU - Saleem, Moin A.

    AU - Lowe, Martin

    AU - Lennon, Rachel

    N1 - Funding for this research was provided by: Wellcome Trust (202860/Z/16/Z) National Institute for Health Research Lowe Syndrome Trust (ML/MU/2012)

    PY - 2019/12/6

    Y1 - 2019/12/6

    N2 - Background: Lowe syndrome and Dent-2 disease are caused by mutations in the OCRL gene, which encodes for an inositol 5-phosphatase. The renal phenotype associated with OCRL mutations typically comprises a selective proximal tubulopathy, which can manifest as Fanconi syndrome in the most extreme cases.Methods: Here, we report a 12-year-old male with nephrotic-range proteinuria and focal segmental glomerulosclerosis on renal biopsy. As a glomerular pathology was suspected, extensive investigation of tubular function was not performed.Results: Surprisingly, whole exome sequencing identified a genetic variant in OCRL (c1467-2A>G) that introduced a novel splice mutation leading to skipping of exon 15. In situ hybridisation of adult human kidney tissue and zebrafish larvae showed OCRL expression in the glomerulus, supporting a role for OCRL in glomerular function. In cultured podocytes, we found that OCRL associated with the linker protein IPIP27A and CD2AP, a protein that is important for maintenance of the podocyte slit diaphragm.Conclusion: Taken together, this work suggests a previously under-appreciated role for OCRL in glomerular function and highlights the importance of investigating tubular function in patients with persistent proteinuria.

    AB - Background: Lowe syndrome and Dent-2 disease are caused by mutations in the OCRL gene, which encodes for an inositol 5-phosphatase. The renal phenotype associated with OCRL mutations typically comprises a selective proximal tubulopathy, which can manifest as Fanconi syndrome in the most extreme cases.Methods: Here, we report a 12-year-old male with nephrotic-range proteinuria and focal segmental glomerulosclerosis on renal biopsy. As a glomerular pathology was suspected, extensive investigation of tubular function was not performed.Results: Surprisingly, whole exome sequencing identified a genetic variant in OCRL (c1467-2A>G) that introduced a novel splice mutation leading to skipping of exon 15. In situ hybridisation of adult human kidney tissue and zebrafish larvae showed OCRL expression in the glomerulus, supporting a role for OCRL in glomerular function. In cultured podocytes, we found that OCRL associated with the linker protein IPIP27A and CD2AP, a protein that is important for maintenance of the podocyte slit diaphragm.Conclusion: Taken together, this work suggests a previously under-appreciated role for OCRL in glomerular function and highlights the importance of investigating tubular function in patients with persistent proteinuria.

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    Preston R, Naylor RW, Stewart G, Bierzynska A, Saleem MA, Lowe M et al. A role for OCRL in glomerular function and disease. Pediatric Nephrology. 2019 Dec 6. https://doi.org/10.1007/s00467-019-04317-4