Common variation in GPC5 is associated with acquired nephrotic syndrome

Okamoto, Koji; Tokunaga, Katsushi; Doi, Kent; Fujita, Toshiro; Suzuki, Hodaka; Katoh, Tetsuo; Watanabe, Tsuyoshi; Nishida, Nao; Mabuchi, Akihiko; Takahashi, Atsushi; Kubo, Michiaki; Maeda, Shiro; Nakamura, Yusuke; Noiri, Eisei

doi:10.1038/ng.792

Cited by 88 publications

(90 citation statements)

References 40 publications

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“…GPC6 encodes a smaller protein (∼350 aa) and contains nov-nsSNVs at positions that are highly conserved (GERP score above 5) in 2 of 16 nonhypermutated tumors as well as in 1 hypermutated tumor. GPC6 encodes a glypican, a class of cell surface coreceptors for proteases implicated in cell growth and division (23)(24)(25).…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing identifies a spectrum of mutation frequencies in advanced and lethal prostate cancers

Kumar

White

MacKenzie

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

236

210

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To catalog protein-altering mutations that may drive the development of prostate cancers and their progression to metastatic disease systematically, we performed whole-exome sequencing of 23 prostate cancers derived from 16 different lethal metastatic tumors and three high-grade primary carcinomas. All tumors were propagated in mice as xenografts, designated the LuCaP series, to model phenotypic variation, such as responses to cancer-directed therapeutics. Although corresponding normal tissue was not available for most tumors, we were able to take advantage of increasingly deep catalogs of human genetic variation to remove most germline variants. On average, each tumor genome contained ∼200 novel nonsynonymous variants, of which the vast majority was specific to individual carcinomas. A subset of genes was recurrently altered across tumors derived from different individuals, including TP53, DLK2, GPC6, and SDF4. Unexpectedly, three prostate cancer genomes exhibited substantially higher mutation frequencies, with 2,000-4,000 novel coding variants per exome. A comparison of castration-resistant and castration-sensitive pairs of tumor lines derived from the same prostate cancer highlights mutations in the Wnt pathway as potentially contributing to the development of castration resistance. Collectively, our results indicate that point mutations arising in coding regions of advanced prostate cancers are common but, with notable exceptions, very few genes are mutated in a substantial fraction of tumors. We also report a previously undescribed subtype of prostate cancers exhibiting "hypermutated" genomes, with potential implications for resistance to cancer therapeutics. Our results also suggest that increasingly deep catalogs of human germline variation may challenge the necessity of sequencing matched tumornormal pairs.

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Section: Discussionmentioning

confidence: 99%

Exome sequencing identifies a spectrum of mutation frequencies in advanced and lethal prostate cancers

Kumar

White

MacKenzie

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

236

210

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“…We also investigated the association between SSNS and all the variable SNPs observed in our study in the established kidney disease genes: GPC5, APOL1, and MYH9. [9][10][11][12] No SNP in these genes was significant.…”

Section: Relationship With Other Kidney Disease Locimentioning

confidence: 92%

“…The median age at diagnosis of the cases was 3 years (range, 1.0-9.5 years). All the study patients responded to [8][9][10][11][12] weeks of oral corticosteroid therapy and were classified by the treating physicians as having SSNS. The samples in the study clustered closely together (Supplemental Figure 1) with one outlier that clustered closest to the European ancestry populations from the 1000 Genomes Project (Supplemental Figure 2).…”

Section: Discovery Cohort Characteristics Of Study Participantsmentioning

confidence: 99%

HLA-DQA1 and PLCG2 Are Candidate Risk Loci for Childhood-Onset Steroid-Sensitive Nephrotic Syndrome

Gbadegesin

Adeyemo

Webb

et al. 2015

Journal of the American Society of Nephrology

128

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Steroid-sensitive nephrotic syndrome (SSNS) accounts for .80% of cases of nephrotic syndrome in childhood. However, the etiology and pathogenesis of SSNS remain obscure. Hypothesizing that coding variation may underlie SSNS risk, we conducted an exome array association study of SSNS. We enrolled a discovery set of 363 persons (214 South Asian children with SSNS and 149 controls) and genotyped them using the Illumina HumanExome Beadchip. Four common single nucleotide polymorphisms (SNPs) in HLA-DQA1 and HLA-DQB1 (rs1129740, rs9273349, rs1071630, and rs1140343) were significantly associated with SSNS at or near the Bonferroni-adjusted P value for the number of single variants that were tested (odds ratio, 2.11; 95% confidence interval, 1.56 to 2.86; P=1.68310 26 (Fisher exact test). Two of these SNPs-the missense variants C34Y (rs1129740) and F41S (rs1071630) in HLA-DQA1-were replicated in an independent cohort of children of white European ancestry with SSNS (100 cases and #589 controls; P=1.42310 217). In the rare variant gene set-based analysis, the best signal was found in PLCG2 (P=7.825310 25). In conclusion, this exome array study identified HLA-DQA1 and PLCG2 missense coding variants as candidate loci for SSNS. The finding of a MHC class II locus underlying SSNS risk suggests a major role for immune response in the pathogenesis of SSNS.

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“…Clinical features of omodysplasia-1 involve short stature and facial dysmorphism. Also, common variation in the GPC5 gene is associated with acquired nephrotic syndrome (5). GPC1 is expressed in the developing and adult brain, and GPC1 knock-out mice have reduced brain size at birth (6).…”

Section: Proteoglycans (Pgs)mentioning

confidence: 99%

Crystal Structure of N-Glycosylated Human Glypican-1 Core Protein

Svensson

Awad

Håkansson

et al. 2012

Journal of Biological Chemistry

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Background:The glypican family of cell-surface proteoglycans regulates growth factor signaling during development through their core proteins and heparan sulfate chains. Results: The crystal structure of N-glycosylated human glypican-1 is described. Conclusion:The structure reveals the complete disulfide bond arrangement for the conserved Cys residues in glypicans. Significance: Increased structural knowledge of glypicans will help elucidate their important functions in shaping animal development.

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Common variation in GPC5 is associated with acquired nephrotic syndrome

Cited by 88 publications

References 40 publications

Exome sequencing identifies a spectrum of mutation frequencies in advanced and lethal prostate cancers

Exome sequencing identifies a spectrum of mutation frequencies in advanced and lethal prostate cancers

HLA-DQA1 and PLCG2 Are Candidate Risk Loci for Childhood-Onset Steroid-Sensitive Nephrotic Syndrome

Crystal Structure of N-Glycosylated Human Glypican-1 Core Protein

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