Focal segmental glomerulosclerosis is associated with a PDSS2 haplotype and, independently, with a decreased content of coenzyme Q10.
Focal segmental glomerulosclerosis (FSGS) and collapsing glomerulopathy are common causes of nephrotic syndrome. Variants in >20 genes, including genes critical for mitochondrial function, have been associated with these podocyte diseases. One such gene, PDSS2, is required for synthesis of the decaprenyl tail of coenzyme Q10 (Q10) in humans. The mouse gene Pdss2 is mutated in the kd/kd mouse model of collapsing glomerulopathy. We examined the hypothesis that human PDSS2 polymorphisms are associated with podocyte diseases. We genotyped 377 patients with primary FSGS or collapsing glomerulopathy, together with 900 controls, for 9 single-nucleotide polymorphisms in the PDSS2 gene in a case-control study. Subjects included 247 African American (AA) and 130 European American (EA) patients and 641 AA and 259 EA controls. Among EAs, a pair of proxy SNPs was significantly associated with podocyte disease, and patients homozygous for one PDSS2 haplotype had a strongly increased risk for podocyte disease. By contrast, the distribution of PDSS2 genotypes and haplotypes was similar in AA patients and controls. Thus a PDSS2 haplotype, which has a frequency of 13% in the EA control population and a homozygote frequency of 1.2%, is associated with a significantly increased risk for FSGS and collapsing glomerulopathy in EAs. Lymphoblastoid cell lines from FSGS patients had significantly less Q10 than cell lines from controls; contrary to expectation, this finding was independent of PDSS2 haplotype. These results suggest that FSGS patients have Q10 deficiency and that this deficiency is manifested in patient-derived lymphoblastoid cell lines.
Dept. of Genetics, Univ. of Pennsylvania School of Medicine, 415 Curie Blvd., Philadelphia, PA 19104. gasserd@mail.med.upenn.edu.
David L
DL
Gasser
Cheryl A
CA
Winkler
Min
M
Peng
Ping
P
An
Louise M
LM
McKenzie
Gregory D
GD
Kirk
Yuchen
Y
Shi
Letian X
LX
Xie
Beth N
BN
Marbois
Catherine F
CF
Clarke
Jeffrey B
JB
Kopp
D000293:Adolescent; D000328:Adult; D019883:Alkyl and Aryl Transferases / Q000235:genetics*; D016175:B-Lymphocyte Subsets / Q000201:enzymology / Q000473:pathology; D016022:Case-Control Studies; D005923:Glomerulosclerosis, Focal Segmental / Q000201:enzymology* / Q000208:ethnology / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000172:deficiency / Q000378:metabolism; D055815:Young Adult
D014451:Ubiquinone; D019883:Alkyl and Aryl Transferases; C540142:prenyl diphosphate synthase, subunit 2, human; C024989:coenzyme Q10
collapsing glomerulopathy; focal segmental glomerulosclerosis; mitochondria; nephrotic syndrome; ubiquinone