Characterization of a novel disease-associated mutation within NPHS1 and its effects on nephrin phosphorylation and signaling

Cooper, Connor J.; Dutta, Nikkita T.; Martín, Claire Emilie; Piscione, Tino D.; Thorner, Paul; Jones, Nina

doi:10.1371/journal.pone.0203905

Cited by 6 publications

(5 citation statements)

References 39 publications

(59 reference statements)

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“…This SNP was predicted to cause amino acid substitution from alanine, an amino acid with a hydrophobic side chain, to threonine, an amino acid with a polar uncharged side chain (Figure 3b). Transmembrane domain is composed of many hydrophobic amino acids and amino acid substitutions in transmembrane domain have been reported to influence gene function due to alteration of the protein localization and interaction with other molecules (Bocharov et al, 2019; Cooper et al, 2018). Therefore, many polymorphisms in transmembrane domain of MC1R protein influence coat color.…”

Section: Resultsmentioning

confidence: 99%

MC1R c.310G>‐ and c.871G > A determine the coat color of Kumamoto sub‐breed of Japanese Brown cattle

Matsumoto

Kojya

Takamuku

et al. 2020

Animal Science Journal

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Domestic animals such as chickens and pigs show various coat colors, which are one of the important factors characterizing breeds and strictly controlled by genetic factors. So far, many genes associated with coat color have been identified (Reissmann & Ludwig, 2013; Steingrímsson, Copeland, & Jenkins, 2006). For example, mutations in tyrosinase gene and its related genes cause albinism, white coat, and skin with pink eyes, due to lack of melanin synthesis (Kamaraj & Purohit, 2014). Melanocortin 1 receptor (MC1R) is another representative responsible for coat color. The encoded protein is a G protein-coupled receptor with seven-pass transmembrane domain controlling melanogenesis. When MC1R is activated by its ligand, α-Melanocyte Stimulating Hormone, it stimulates melanocytes to make brown or black eumelanin in addition to yellow or red pheomelanin via cAMP signaling cascade. If MC1R is not activated, eumelanin synthesis is decreased and melanocytes mainly produce pheomelanin (García-Borrón, Abdel-Malek, & Jiménez-Cervantes, 2014; Wolf Horrell et al., 2016). Alterations of MC1R function and their effects on coat color have been analyzed in various animal species including horses, pigs, and chickens (Andersson, 2003). Lots of polymorphisms have also been identified in bovine MC1R gene on BTA18. Xi et al. (2012) and Zhang et al. (2014) have reported 23 polymorphisms, including 15 non-synonymous mutations and one frameshift mutation, in the coding region of MC1R gene of Asian cattle. Although their effects on the coat color phenotype are not fully

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Section: Resultsmentioning

confidence: 99%

MC1R c.310G>‐ and c.871G > A determine the coat color of Kumamoto sub‐breed of Japanese Brown cattle

Matsumoto

Kojya

Takamuku

et al. 2020

Animal Science Journal

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“…S1 ). Because previous studies by ourselves and others involving biotin-mediated labeling of cell surface proteins showed that the upper band represented the majority of NEPHRIN protein on the cell surface 17 , 19 , the R460Q mutant was likely to be localized on the cell surface of HEK293 cells. Thus, the underlying mechanisms for the pathogenesis may differ between Patient 3 (R460Q) and Patient 0 (E725D).…”

Section: Resultsmentioning

confidence: 87%

Impaired NEPHRIN localization in kidney organoids derived from nephrotic patient iPS cells

Ohmori

Tanigawa

et al. 2021

Sci Rep

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Mutations in the NPHS1 gene, which encodes NEPHRIN, cause congenital nephrotic syndrome, resulting from impaired slit diaphragm (SD) formation in glomerular podocytes. We previously reported NEPHRIN and SD abnormalities in the podocytes of kidney organoids generated from patient-derived induced pluripotent stem cells (iPSCs) with an NPHS1 missense mutation (E725D). However, the mechanisms underlying the disease may vary depending on the mutations involved, and thus generation of iPSCs from multiple patients is warranted. Here we established iPSCs from two additional patients with different NPHS1 mutations and examined the podocyte abnormalities in kidney organoids derived from these cells. One patient had truncating mutations, and NEPHRIN was undetectable in the resulting organoids. The other patient had a missense mutation (R460Q), and the mutant NEPHRIN in the organoids failed to accumulate on the podocyte surface to form SD precursors. However, the same mutant protein behaved normally when overexpressed in heterologous cells, suggesting that NEPHRIN localization is cell context-dependent. The localization of another SD-associated protein, PODOCIN, was impaired in both types of mutant organoids in a cell domain-specific manner. Thus, the new iPSC lines and resultant kidney organoids will be useful resources for dissecting the disease mechanisms, as well as for drug development for therapies.

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“…MC1R, a known key determinant of color phenotype in bovine [46]. The transmembrane domain is composed of several polar and non-polar amino acid changes in the transmembrane domain have been described to regulate gene function due to variation of the protein localization and interaction with different molecules [47,48]. Due to SNP changes (c.844C>A, p281T>N) might alter the function and the structure of MC1R protein.…”

Section: Discussionmentioning

confidence: 99%

Molecular characterization of coat color gene in Sahiwal versus Karan Fries bovine

Goud

Upadhyay

Pichili

et al. 2021

Journal of Genetic Engineering and Biotechnology

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Background Melanocortin-1-receptor gene (MC1R) plays a significant role in signaling cascade of melanin production. In cattle, the coat colors, such as red and black, are an outcome of eumelanin and pheomelanin pigments, respectively. The coat colors have become critical factors in the animal selection process. This study is therefore aimed at the molecular characterization of reddish-brown coat-colored Sahiwal cattle in comparison to the black and white-colored Karan Fries. Results The Sequence length of the MC1R gene was 954 base pairs in Sahiwal cattle. The sequences were examined and submitted to GenBank Acc.No. MG373575 to MG373605. Alignment of both (Sahiwal and Karan Fries) protein sequences by applying ClustalO multiple sequence alignment programs revealed 99.8–96.8% sequence similarity within the bovine. MC1R gene phylogenetic studies were analyzed by MEGA X. The gene MC1R tree, protein confines, and hereditary difference of cattle were derived from Ensemble Asia Cow Genome Browser 97. One unique single-nucleotide polymorphism (c.844C>A) (SNP) was distinguished. Single amino acid changes were detected in the seventh transmembrane structural helix region, with SNP at p.281 T>N of MC1R gene in Karan Fries cattle. Conclusions In this current research, we first distinguished the genomic sequence of the MC1R gene regions that showed evidence of coat variation between Indian indigenous Sahiwal cattle breed correlated with crossbreed Karan Fries. These variations were found in the Melanocortin 1 receptor coding regions of the diverse SNPs. The conclusions of this research provide new insights into understanding the coat color variation in crossbreed compared to the Indian Sahiwal cattle. Graphical abstract

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Characterization of a novel disease-associated mutation within NPHS1 and its effects on nephrin phosphorylation and signaling

Cited by 6 publications

References 39 publications

MC1R c.310G>‐ and c.871G > A determine the coat color of Kumamoto sub‐breed of Japanese Brown cattle

MC1R c.310G>‐ and c.871G > A determine the coat color of Kumamoto sub‐breed of Japanese Brown cattle

Impaired NEPHRIN localization in kidney organoids derived from nephrotic patient iPS cells

Molecular characterization of coat color gene in Sahiwal versus Karan Fries bovine

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