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NPHP4 mutation is linked to cerebello-oculo-renal syndrome and male infertility

Authors

  • A.M. Alazami,

    1. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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    • These authors have contributed equally and should be considered co-first authors.

  • M.J. Alshammari,

    1. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
    2. Department of Pediatrics
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    • These authors have contributed equally and should be considered co-first authors.

  • M. Baig,

    1. Department of Pathology and Laboratory Medicine
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  • M.A. Salih,

    1. Department of Pediatrics
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  • H.H. Hassan,

    1. Department of Radiology, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh, Saudi Arabia
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  • F.S. Alkuraya

    Corresponding author
    1. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
    2. Department of Pediatrics
    3. Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
    • Corresponding author: Prof Fowzan S.

      Alkuraya, MD, FAAP, FACMG,

      Developmental Genetics Unit, King

      Faisal Specialist Hospital and Research

      Center, MBC-03, Riyadh 11211, Saudi

      Arabia.

      Tel.: +966 1 442 7875;

      fax: +966 1 442 4585;

      e-mail: falkuraya@kfshrc.edu.sa[PO BOX 3354]

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  • The authors declare no conflict of interest.

Abstract

Nephronophthisis is the most common genetic cause of renal failure in children and young adults. It is genetically heterogeneous and can be seen in isolation or in combination with other ciliopathy phenotypes. Here we report an index case where nephronophthisis is associated with oculomotor apraxia and cerebellar abnormalities, consistent with the clinical diagnosis of cerebello-oculo-renal syndrome. Prompted by a family history of an uncle with early onset end stage renal failure and infertility, we performed semen analysis on the index. This revealed marked reduction in the count of motile sperms as well as multiple abnormalities in the head and tail. Autozygome-guided mutation analysis followed by exome sequencing and segregation analysis revealed a homozygous truncating mutation in NPHP4, indicating that mutations of this gene can on rare occasions cause cerebello-oculo-renal syndrome. Our finding of severe male infertility in a family with NPHP4 truncation is strongly supported by the mouse model and, to our knowledge, is the first reported male infertility phenotype in association with NPHP4 or any other nephrocystin in humans.

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