Simplet/Fam53b is required for Wnt signal transduction by regulating β-catenin nuclear localization

Kızıl, Çağhan; Küchler, Beate; Yan, Jia-Jiun; Özhan, Günes; Moro, Enrico; Argenton, Francesco; Brand, Michael; Weidinger, Gilbert; Antos, Christopher L.

doi:10.1242/dev.108415

Cited by 32 publications

(29 citation statements)

References 69 publications

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“…The comparison with eQTL data sets revealed a colocalization of MPB-risk variants with known regulatory variants ( r 2 >0.5 between eQTL single nucleotide polymorphism (SNP) and MPB lead SNP) in 25 loci. For 10 of these 25 loci, previous studies have found an association between the MPB lead SNP itself and gene expression for example, of CRHR1 , which encodes for a receptor for corticotropin releasing hormone (CRH), a known hair growth inhibitor and catagen inductor17, FAM53B a positive regulator of WNT/beta-catenin-signalling18 and other genes, for example, ANXA2 , SUCNR1 , WARS2 that have not yet been associated with hair biology (Supplementary Table 2). Detailed functional follow-up studies are now warranted to confirm these regulatory interactions, and to investigate the contribution of these candidate genes to the development of key MPB pathophysiological signs.…”

Section: Resultsmentioning

confidence: 99%

Meta-analysis identifies novel risk loci and yields systematic insights into the biology of male-pattern baldness

et al. 2017

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Male-pattern baldness (MPB) is a common and highly heritable trait characterized by androgen-dependent, progressive hair loss from the scalp. Here, we carry out the largest GWAS meta-analysis of MPB to date, comprising 10,846 early-onset cases and 11,672 controls from eight independent cohorts. We identify 63 MPB-associated loci (P<5 × 10−8, METAL) of which 23 have not been reported previously. The 63 loci explain ∼39% of the phenotypic variance in MPB and highlight several plausible candidate genes (FGF5, IRF4, DKK2) and pathways (melatonin signalling, adipogenesis) that are likely to be implicated in the key-pathophysiological features of MPB and may represent promising targets for the development of novel therapeutic options. The data provide molecular evidence that rather than being an isolated trait, MPB shares a substantial biological basis with numerous other human phenotypes and may deserve evaluation as an early prognostic marker, for example, for prostate cancer, sudden cardiac arrest and neurodegenerative disorders.

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Section: Resultsmentioning

confidence: 99%

Meta-analysis identifies novel risk loci and yields systematic insights into the biology of male-pattern baldness

et al. 2017

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“…For example, Wnt signaling has been implicated in kidney development and disease 24 . FAM53B controls βcatenin nuclear localization 25 , a key component of Wnt signaling. β-catenin translocation into the nucleus allows for activation of target genes via interaction with TCF transcription factors 26,27 .…”

Section: Discussionmentioning

confidence: 99%

Sex-specific and pleiotropic effects underlying kidney function identified from GWAS meta-analysis

Graham

Nielsen

Zawistowski

et al. 2018

Preprint

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Chronic Kidney Disease (CKD) is a growing health burden currently affecting 10-15% of adults worldwide. Estimated glomerular filtration rate (eGFR) as a marker of kidney function is commonly used to diagnose CKD. Previous genome-wide association study (GWAS) metaanalyses of CKD and eGFR or related phenotypes have identified a number of variants associated with kidney function, but these only explain a fraction of the variability in kidney phenotypes attributed to genetic components. To extend these studies, we analyzed data from the Nord-Trøndelag Health Study (HUNT), which is more densely imputed than previous studies, and performed a GWAS meta-analysis of eGFR with publicly available summary statistics, more than doubling the sample size of previous meta-analyses. We identified 147 loci (53 novel loci) associated with eGFR, including genes involved in transcriptional regulation, kidney development, cellular signaling, metabolism, and solute transport. Moreover, genes at these loci show enriched expression in urogenital tissues and highlight gene sets known to play a role in kidney function. In addition, sex-stratified analysis identified three regions (prioritized genes: PPM1J, MCL1, and SLC47A1) with more significant effects in women than men. Using genetic risk scores constructed from these eGFR meta-analysis results, we show that associated variants are generally predictive of CKD but improve detection only modestly compared with other known clinical risk factors. Collectively, these results yield additional insight into the genetic factors underlying kidney function and progression to CKD. Graham et al.

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“…The best-known member of the family is FAM53B, a controller of tissue development and cell proliferation [33, 37]. FAM53B is required for Wnt signaling, a pathway involved in epithelial-to-mesenchymal transition and subsequent metastasis in breast cancer [38–40]. FAM53B has also been identified as a critical gene in the prognosis of multiple myeloma in a transcriptional network analysis [41].…”

Section: Discussionmentioning

confidence: 99%

TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer

Fagerholm¹,

Khan²,

Schmidt³

et al. 2017

Oncotarget

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TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a two-stage SNP association study to detect variants associated with breast cancer survival in a TP53-dependent manner. Initially, a genome-wide study (n = 575 cases) was conducted to discover candidate SNPs for genotyping and validation in the Breast Cancer Association Consortium (BCAC). The SNPs were then tested for interaction with tumor TP53 status (n = 4,610) and anthracycline treatment (n = 17,828). For SNPs interacting with anthracycline treatment, siRNA knockdown experiments were carried out to validate candidate genes.In the test for interaction between SNP genotype and TP53 status, we identified one locus, represented by rs10916264 (p(interaction) = 3.44 05E010-5; FDR-adjusted p = 0.0011) in estrogen receptor (ER) positive cases. The rs10916264 AA genotype associated with worse survival among cases with ER-positive, TP53-positive tumors (hazard ratio [HR] 2.36, 95% confidence interval [C.I] 1.45 - 3.82). This is a cis-eQTL locus for FBXO28 and TP53BP2; expression levels of these genes were associated with patient survival specifically in ER-positive, TP53-mutated tumors. Additionally, the SNP rs798755 was associated with survival in interaction with anthracycline treatment (p(interaction) = 9.57 05E010-5, FDR-adjusted p = 0.0130). RNAi-based depletion of a predicted regulatory target gene, FAM53A, indicated that this gene can modulate doxorubicin sensitivity in breast cancer cell lines.If confirmed in independent data sets, these results may be of clinical relevance in the development of prognostic and predictive marker panels for breast cancer.

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Simplet/Fam53b is required for Wnt signal transduction by regulating β-catenin nuclear localization

Cited by 32 publications

References 69 publications

Meta-analysis identifies novel risk loci and yields systematic insights into the biology of male-pattern baldness

Meta-analysis identifies novel risk loci and yields systematic insights into the biology of male-pattern baldness

Sex-specific and pleiotropic effects underlying kidney function identified from GWAS meta-analysis

TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer

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