@article{57d24a76e9a0451899cb4a4cc0c02888,
title = "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.",
keywords = "gene expression, genetic mutations, pediatric nephrology, pre-mRNA splicing, SON haploinsufficiency, INTELLECTUAL-DISABILITY, BRANCHING MORPHOGENESIS, KIDNEY, MUTATIONS, PKD1, IDENTIFICATION, CHILDREN, PROTEIN",
author = "Jung-Hyun Kim and Park, {Eun Young} and David Chitayat and Stachura, {David L.} and Jorg Schaper and Kristin Lindstrom and Tamison Jewett and Dagmar Wieczorek and Draaisma, {Jos M.} and Margje Sinnema and Christianne Hoeberigs and Maja Hempel and Bachman, {Kristine K.} and Seeley, {Andrea H.} and Stone, {Joshua K.} and Kong, {Hyun Kyung} and Lana Vukadin and Alexander Richard and Shinde, {Deepali N.} and Kirsty McWalter and Si, {Yue Cindy} and Ganka Douglas and Ssang-Taek Lim and Vissers, {Lisenka E. L. M.} and Mathieu Lemaire and Ahn, {Eun-Young Erin}",
note = "Funding Information: We are deeply grateful to the patients and their families for participating in this study. We thank Margot R.F. Reinders (Radboud University Medical Center, The Netherlands) for her help in summarizing clinical features of a patient, and Megan T. Cho for her help in connecting with collaborators. This work was supported by the US National Institutes of Health Grants (CA190688 to E-YEA) and an Institutional Fund from the University of South Alabama Mitchell Cancer Institute (to E-YEA). ML is supported by New Investigators Awards from the Kidney Research Scientist Core Education and National Training Program (KRESCENT) and the Canadian Child Health Clinician Scientist Program ( CCHCSP ). Funding Information: We are deeply grateful to the patients and their families for participating in this study. We thank Margot R.F. Reinders (Radboud University Medical Center, The Netherlands)for her help in summarizing clinical features of a patient, and Megan T. Cho for her help in connecting with collaborators. This work was supported by the US National Institutes of Health Grants (CA190688 to E-YEA)and an Institutional Fund from the University of South Alabama Mitchell Cancer Institute (to E-YEA). ML is supported by New Investigators Awards from the Kidney Research Scientist Core Education and National Training Program (KRESCENT)and the Canadian Child Health Clinician Scientist Program (CCHCSP). Funding Information: We are deeply grateful to the patients and their families for participating in this study. We thank Margot R.F. Reinders (Radboud University Medical Center, The Netherlands) for her help in summarizing clinical features of a patient, and Megan T. Cho for her help in connecting with collaborators. This work was supported by the US National Institutes of Health Grants (CA190688 to E-YEA) and an Institutional Fund from the University of South Alabama Mitchell Cancer Institute (to E-YEA). ML is supported by New Investigators Awards from the Kidney Research Scientist Core Education and National Training Program (KRESCENT) and the Canadian Child Health Clinician Scientist Program (CCHCSP). Publisher Copyright: {\textcopyright} 2019 International Society of Nephrology",
year = "2019",
month = jun,
doi = "10.1016/j.kint.2019.01.025",
language = "English",
volume = "95",
pages = "1494--1504",
journal = "Kidney International",
issn = "0085-2538",
publisher = "Elsevier Science",
number = "6",
}