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Short Report
Homozygous mutation in NUP107 leads to microcephaly with steroid-resistant nephrotic condition similar to Galloway-Mowat syndrome
  1. Rasim Ozgur Rosti1,
  2. Bethany N Sotak1,
  3. Stephanie L Bielas2,
  4. Gifty Bhat3,4,
  5. Jennifer L Silhavy1,
  6. Ayca Dilruba Aslanger5,
  7. Umut Altunoglu6,
  8. Ilmay Bilge7,
  9. Mehmet Tasdemir7,
  10. Amanda D Yzaguirrem1,
  11. Damir Musaev1,
  12. Sofia Infante1,
  13. Whitney Thuong1,
  14. Isaac Marin-Valencia3,
  15. Stanley F Nelson8,
  16. Hulya Kayserili5,9,
  17. Joseph G Gleeson1,3
  1. 1 Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, California, USA
  2. 2 Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan
  3. 3 Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA
  4. 4 Division of Pediatric Genetics
    , The Children’s Hospital at Montefiore, Bronx, Bronx, New York, USA
  5. 5 Department of Medical Genetics, Koç University Hospital, Istanbul 34010, Turkey
  6. 6 Department Medical Genetics, Istanbul University, Istanbul Medical Faculty, Istanbul, Turkey
  7. 7 Department of Pediatric Nephrology, Koç University Hospital, Istanbul, Turkey
  8. 8 Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA
  9. 9 Department of Medical Genetics, Koç University, School of Medicine (KUSoM), Istanbul, Turkey
  1. Correspondence to Dr Joseph G Gleeson, Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Department of Neurosciences University of California, San DiegoLa Jolla, CA 92093, USA; jogleeson{at}ucsd.edu

Abstract

Background Microcephaly with nephrotic syndrome is a rare co-occurrence, constituting the Galloway-Mowat syndrome (GAMOS), caused by mutations in WDR73 (OMIM: 616144). However, not all patients harbour demonstrable WDR73 deleterious variants, suggesting that there are other yet unidentified factors contributing to GAMOS aetiology.

Methods Autozygosity mapping and candidate analysis was used to identify deleterious variants in consanguineous families. Analysis of patient fibroblasts was used to study splicing and alterations in cellular function.

Results In two consanguineous families with five affected individuals from Turkey with a GAMOS-like presentation, we identified a shared homozygous variant leading to partial exon 4 skipping in nucleoporin, 107-KD (NUP107). The founder mutation was associated with concomitant reduction in NUP107 protein and in the obligate binding partner NUP133 protein, as well as density of nuclear pores in patient cells.

Conclusion Recently, NUP107 was suggested as a candidate in a family with nephrotic syndrome and developmental delay. Other NUP107-reported cases had isolated renal phenotypes. With the addition of these individuals, we implicate an allele-specific critical role for NUP107 in the regulation of brain growth and a GAMOS-like presentation.

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Footnotes

  • Contributors ADY, ADA, HK, IB, MT, ROR and UA identified subjects for study; BNS, DM JLS, ROR, SLB, SI, WT identified genetic variants and performed cell culture and sequence analysis; ROR, GB and IM-V contributed to the clinical interpretation and helped write the manuscript; SFN performed SNP analysis and interpretation; HK and JGG supervised the project.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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