RT Journal
A1 Yeo, Nan Cher
A1 O’Meara, Caitlin C.
A1 Bonomo, Jason A.
A1 Veth, Kerry N.
A1 Tomar, Ritu
A1 Flister, Michael J.
A1 Drummond, Iain A.
A1 Bowden, Donald W.
A1 Freedman, Barry I.
A1 Lazar, Jozef
A1 Link, Brian A.
A1 Jacob, Howard J.
T1 Shroom3 contributes to the maintenance of the glomerular filtration barrier integrity
JF Genome Research 
JO Genome Research 
YR 2015 
FD January 01 
VO 25 
IS 1 
SP 57 
OP 65 
DO 10.1101/gr.182881.114 
UL http://genome.cshlp.org/content/25/1/57.abstract 
AB Genome-wide association studies (GWAS) identify regions of the genome correlated with disease risk but are restricted in their ability to identify the underlying causative mechanism(s). Thus, GWAS are useful “roadmaps” that require functional analysis to establish the genetic and mechanistic structure of a particular locus. Unfortunately, direct functional testing in humans is limited, demonstrating the need for complementary approaches. Here we used an integrated approach combining zebrafish, rat, and human data to interrogate the function of an established GWAS locus (SHROOM3) lacking prior functional support for chronic kidney disease (CKD). Congenic mapping and sequence analysis in rats suggested Shroom3 was a strong positional candidate gene. Transferring a 6.1-Mb region containing the wild-type Shroom3 gene significantly improved the kidney glomerular function in FHH (fawn-hooded hypertensive) rat. The wild-type Shroom3 allele, but not the FHH Shroom3 allele, rescued glomerular defects induced by knockdown of endogenous shroom3 in zebrafish, suggesting that the FHH Shroom3 allele is defective and likely contributes to renal injury in the FHH rat. We also show for the first time that variants disrupting the actin-binding domain of SHROOM3 may cause podocyte effacement and impairment of the glomerular filtration barrier.