Fam20C in Human Diseases: Emerging Biological Functions and Therapeutic Implications

Rong-sheng, Xu; Tan, Huidan; Zhang, Jiahui; Yuan, Zhaoxin; Xie, Qiang; Zhang, Lan

doi:10.3389/fmolb.2021.790172

Cited by 13 publications

(9 citation statements)

References 52 publications

(83 reference statements)

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“…According to available information, 53 distinct variations (identified as pathogenic by ClinVar) have been documented in cases of Raine syndrome, encompassing splicing defects, frameshift, missense, non-sense mutations (causing truncated proteins), and chromosomal rearrangements, both lethal and non-lethal. In addition to the variant found in our case c.1291C>T (p.Gln431*), the variant c.1135G>A (p.Gly379Arg) was identified in one lethal homozygous case and one non-lethal case, possibly associated with severe cases of Raine syndrome ( Xu et al, 2021 ). While consanguinity was typically observed in most cases, our case involved parents who were not related through consanguineous marriage (Mameli, C.,2020).…”

Section: Discussionsupporting

confidence: 50%

“… Simpson et al (2009) were the first to report on non-lethal Raine syndrome when the patients were 9 and 11 years old. Approximately 70 cases of Raine syndrome (40 cases of lethal Raine Syndrome and 30 non-lethal cases) have been reported ( Xu, R., et al, 2021 ), with a prevalence of 1/100,000 cases, requiring continuous investigations to understand better the syndrome, its functioning mechanism, and possible treatment ( Rameh, G., et al, 2022 ). Raine et al described in 1989 an unknown multiple congenital anomalies syndrome in a newborn who died soon after birth, later on, identified as Raine Syndrome ( Hernández-Zavala, A., et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Compound heterozygous FAM20C gene variants in a patient with severe Raine syndrome: a case report

Chirtes¹,

Bogliș

Tóth³

et al. 2023

Front. Genet.

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Raine syndrome is a congenital disorder caused by biallelic mutations in the FAM20C gene. While most diagnosed cases of the syndrome are lethal in the first few months of life, there are also reports of non-lethal cases with Raine syndrome. The characteristic of this syndrome is typical facial dysmorphism and generalized osteosclerosis, as well as possible intracranial calcification, hearing loss, and seizures. We report a case of a 4-day-old patient at the time of examination, born with a distinct facial dysmorphism, short neck, narrow chest, and curved tibia. The parents, affirmative gypsy and non-consanguineous, had a previous male child born with the same phenotype who died at 4 months old. The computed tomography scan revealed choanal atresia, while transfontanelar ultrasound showed hypoplasia of the frontal and temporal lobes, corpus callosum dysgenesis, and multiple areas of intracranial hyperechogenicity. The chest X-Ray revealed generalized increased bone density. A skeletal disorders gene panel was performed which identified two variants in the FAM20C gene: a pathogenic variant c.1291C>T (p.Gln431*) and a likely pathogenic variant (c.1135G>A) (p.Gly379Arg), confirming the clinical diagnosis. The parents were also tested, and each was found to carry one of the variants. The particularity of this case is the severe phenotype in a compound heterozygous case that consists of FAM20C c.1291C>T (p.Gln431*) variant that has recently been reported in the literature. Also, our case is one of the few compound-heterozygous mutations in the FAM20C gene that has been described in a non-consanguineous marriage.

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Section: Discussionsupporting

confidence: 50%

Section: Introductionmentioning

confidence: 99%

Compound heterozygous FAM20C gene variants in a patient with severe Raine syndrome: a case report

Chirtes¹,

Bogliș

Tóth³

et al. 2023

Front. Genet.

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“…This pathway also includes notable cardiovascular risk proteins, including PCSK9 and FGF23, which interact with IGF and IGFBPs via FAM20C. 53 While causal effects for IGFBPs on the tested diseases were not supported in our MR analysis, IGFBP2 and IGFBP6 were implicated with T2D and CKD, respectively, in our mediation framework. In the RCTs, many IGF-related proteins were significantly associated with outcomes ( Figure 4B and D ).…”

Section: Resultsmentioning

confidence: 73%

Identification of plasma proteomic markers underlying polygenic risk of type 2 diabetes and related comorbidities

Loesch,

Garg,

Matelska

et al. 2024

Preprint

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Introduction: Type 2 diabetes (T2D) is a heterogeneous disorder for which disease-causing pathways are incompletely understood. Here, we mapped genetic risk for T2D and its comorbidities to proteins, mechanistic pathways and clinical outcomes using proteogenomic data from a population-scale biobank and two randomized controlled trials. Methods: We tested polygenic scores (PGS) for T2D and its cardiometabolic comorbidities, plus five partitioned T2D PGS (beta cell, lipodystrophy, liver lipid, obesity, and liver lipid), for association with 2,922 circulating proteins in 54,306 multi-ancestry participants (of which 42,452 were unrelated and without prevalent cardiometabolic disease) from the UK Biobank (UKB). Then, we tested the PGS-associated proteins for association with incident cardiometabolic complications in two cardiovascular outcome trials among T2D patients with proteogenomic data: EXSCEL (N=2,823) and DECLARE-TIMI 58 (N=915). We assessed causality using two-sample Mendelian randomization and mediation. Results: We identified 839 unique proteins significantly associated with any T2D PGS and 1,005 proteins that were associated with at least one cardiometabolic PGS. Some PGS-associated proteins such as TFF3, EFEMP1, and MMP12 were in turn associated with renal and cardiovascular trial outcomes. PGS association patterns revealed shared pathways, e.g., complement cascade, cholesterol metabolism, IGF signaling. The proteins underlying these pathways, such as LPA, C1S, and IGFBP2, were consistently associated with clinical trial outcomes or identified via causal inference. Conclusions: This proteogenomic study revealed proteins and mechanistic pathways underlying T2D and related comorbidities, advancing our understanding of T2D pathobiology and identifying putative biomarkers. All our results are available in an online data portal (https://public.cgr.astrazeneca.com/t2d-pgs/v1/).

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“…Finally, we identified other potentially novel regulators of anti-tumor immune response such as FAM20C, RFPL2, MAMDC2, SPATA2 in melanoma cells ( Figs. 3C, S3F-S3G and Table S3 ) (Lee et al, 2020; Schlicher et al, 2016; Xu et al, 2021). Integration of enhancer gains with gene expression data showed concomitant upregulation of gene expression of a subset of enhancer-target genes at the pre-treatment stage ( Figs.…”

Section: Resultsmentioning

confidence: 99%

Enhancer Reprogramming in Melanoma Immune Checkpoint Therapy Resistance

Maitituoheti

Shi

Tang

et al. 2022

Preprint

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Immune checkpoint blockade (ICB) therapy has improved long-term survival for patients with advanced melanoma. However, there is critical need to identify potential biomarkers of response and actionable strategies to improve response rates. Through generation and analysis of 148 chromatin modification maps for 36 melanoma samples from patients treated with anti-PD-1, we identified significant enrichment of active enhancer states in non-responders at baseline. Analysis of an independent cohort of 20 samples identified a set of 437 enhancers that predicted response to anti-PD-1 therapy (Area Under the Curve of 0.8417). The activated non-responder enhancers marked a group of key regulators of several pathways in melanoma cells (including c-MET, TGFβ, EMT and AKT) that are known to mediate resistance to ICB therapy and several checkpoint receptors in T cells. Epigenetic editing experiments implicated involvement of c-MET enhancers in the modulation of immune response. Finally, inhibition of enhancers and repression of these pathways using bromodomain inhibitors along with anti-PD-1 therapy significantly decreased melanoma tumor burden and increased T-cell infiltration. Together, these findings identify a potential enhancer-based biomarker of resistance to anti-PD-1 and suggest enhancer blockade in combination with ICB as a potential strategy to improve responses.

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Fam20C in Human Diseases: Emerging Biological Functions and Therapeutic Implications

Cited by 13 publications

References 52 publications

Compound heterozygous FAM20C gene variants in a patient with severe Raine syndrome: a case report

Compound heterozygous FAM20C gene variants in a patient with severe Raine syndrome: a case report

Identification of plasma proteomic markers underlying polygenic risk of type 2 diabetes and related comorbidities

Enhancer Reprogramming in Melanoma Immune Checkpoint Therapy Resistance

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