Homozygous mutation in NUP107 leads to microcephaly with steroid-resistant nephrotic condition similar to Galloway-Mowat syndrome
- J Med Genet. 2017 Jun;54(6):399-403. doi: 10.1136/jmedgenet-2016-104237.
- 1. Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
- 2. Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan.
- 3. Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA.
- 4. Division of Pediatric Genetics , The Children's Hospital at Montefiore, Bronx, Bronx, New York, USA.
- 5. Department of Medical Genetics, Koç University Hospital, Istanbul 34010, Turkey.
- 6. Department Medical Genetics, Istanbul University, Istanbul Medical Faculty, Istanbul, Turkey.
- 7. Department of Pediatric Nephrology, Koç University Hospital, Istanbul, Turkey.
- 8. Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
- 9. Department of Medical Genetics, Koç University, School of Medicine (KUSoM), Istanbul, Turkey.
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.