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

TY - JOUR

T1 - SON haploinsufficiency causes impaired pre-mRNA splicing of CAKUT genes and heterogeneous renal phenotypes

AU - Kim, Jung-Hyun

AU - Park, Eun Young

AU - Chitayat, David

AU - Stachura, David L

AU - Schaper, Jörg

AU - Lindstrom, Kristin

AU - Jewett, Tamison

AU - Wieczorek, Dagmar

AU - Draaisma, Jos M

AU - Sinnema, Margje

AU - Hoeberigs, Christianne

AU - Hempel, Maja

AU - Bachman, Kristine K

AU - Seeley, Andrea H

AU - Stone, Joshua K

AU - Kong, Hyun Kyung

AU - Vukadin, Lana

AU - Richard, Alexander

AU - Shinde, Deepali N

AU - McWalter, Kirsty

AU - Si, Yue Cindy

AU - Douglas, Ganka

AU - Lim, Ssang-Taek

AU - Vissers, Lisenka E L M

AU - Lemaire, Mathieu

AU - Ahn, Eun-Young Erin

N1 - Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

PY - 2019/6

Y1 - 2019/6

N2 - 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.

AB - 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.

U2 - 10.1016/j.kint.2019.01.025

DO - 10.1016/j.kint.2019.01.025

M3 - SCORING: Journal article

C2 - 31005274

VL - 95

SP - 1494

EP - 1504

JO - KIDNEY INT

JF - KIDNEY INT

SN - 0085-2538

IS - 6

ER -