SON haploinsufficiency causes impaired pre-mRNA splicing of CAKUT genes and heterogeneous renal phenotypes.

Abstract

Although genetic testing is increasingly used in clinical nephrology, a large number of patients with congenital abnormalities of the kidney and urinary tract (CAKUT) remain undiagnosed with current gene panels. Therefore, careful curation of novel genetic findings is key to improving diagnostic yields. We recently described a novel intellectual disability syndrome caused by de novo heterozygous loss-of-function mutations in the gene encoding the splicing factor SON. Here, we show that many of these patients, including two previously unreported, exhibit a wide array of kidney abnormalities. Detailed phenotyping of 14 patients with SON haploinsufficiency identified kidney anomalies in 8 patients, including horseshoe kidney, unilateral renal hypoplasia, and renal cysts. Recurrent urinary tract infections, electrolyte disturbances, and hypertension were also observed in some patients. SON knockdown in kidney cell lines leads to abnormal pre-mRNA splicing, resulting in decreased expression of several established CAKUT genes. Furthermore, these molecular events were observed in patient-derived cells with SON haploinsufficiency. Taken together, our data suggest that the wide spectrum of phenotypes in patients with a pathogenic SON mutation is a consequence of impaired pre-mRNA splicing of several CAKUT genes. We propose that genetic testing panels designed to diagnose children with a kidney phenotype should include the SON gene.

• Authors: Jung-Hyun Kim, Eun Young Park, David Chitayat, David L Stachura, Jörg Schaper, Kristin Lindstrom, Tamison Jewett, Dagmar Wieczorek, Jos M Draaisma, Margje Sinnema, Christianne Hoeberigs, Maja Hempel, Kristine K Bachman, Andrea H Seeley, Joshua K Stone, Hyun Kyung Kong, Lana Vukadin, Alexander Richard, Deepali N Shinde, Kirsty McWalter, Yue Cindy Si, Ganka Douglas, Ssang-Taek Lim, Lisenka E L M Vissers, Mathieu Lemaire, Eun-Young Erin Ahn
• Journal: Kidney international (Kidney Int) Vol. 95 Issue 6 Pg. 1494-1504 (06 2019) ISSN: 1523-1755 [Electronic] United States
• PMID: 31005274 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Chemical References

• DNA-Binding Proteins
• Minor Histocompatibility Antigens
• RNA Precursors
• SON protein, human
• TRPP Cation Channels
• polycystic kidney disease 1 protein
• polycystic kidney disease 2 protein

Topics

• Adolescent
• Adult
• Child
• Child, Preschool
• DNA-Binding Proteins (genetics, metabolism)
• Female
• Genetic Testing (methods)
• HEK293 Cells
• Haploinsufficiency
• Humans
• Male
• Minor Histocompatibility Antigens (genetics, metabolism)
• RNA Precursors (genetics, metabolism)
• RNA Splicing (genetics)
• TRPP Cation Channels (genetics)
• Urogenital Abnormalities (diagnosis, genetics)
• Vesico-Ureteral Reflux (diagnosis, genetics)