A novel <i>CYCS</i> mutation in the α‐helix of the CYCS C‐terminal domain causes non‐syndromic thrombocytopenia

Uchiyama, Yuri; Yanagisawa, Kunio; Kunishima, Shinji; Shiina, Masaaki; Ogawa, Yoshiyuki; Nakashima, Mitsuko; Hirato, Junko; Imagawa, Eri; Fujita, Atsushi; Hamanaka, Kohei; Miyatake, Satoko; Mitsuhashi, Satomi; Takata, Atsushi; Miyake, Noriko; Ogata, Kazuhiro; Handa, Hiroshi; Matsumoto, Naomichi; Mizuguchi, Takeshi

doi:10.1111/cge.13423

Cited by 24 publications

(19 citation statements)

References 14 publications

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“…S32) overlaps the CYCS gene. This gene codes for cytochrome C: a small heme protein that plays a crucial role in the electron transport chain in mitochondria, and has been associated with various blood-related diseases, like thrombocytopenia (Morison et al ., 2008; De Rocco et al ., 2014; Uchiyama et al ., 2018). Another top candidate region (chr12:108.24-108.34Mb, Fig.…”

Section: Resultsmentioning

confidence: 99%

Detecting adaptive introgression in human evolution using convolutional neural networks

Gower

Picazo

Fumagalli

et al. 2020

Preprint

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Studies in a variety of species have shown evidence for positively selected variants introduced into one population via introgression from another, distantly related population—a process known as adaptive introgression. However, there are few explicit frameworks for jointly modelling introgression and positive selection, in order to detect these variants using genomic sequence data. Here, we develop an approach based on convolutional neural networks (CNNs). CNNs do not require the specification of an analytical model of allele frequency dynamics, and have outperformed alternative methods for classification and parameter estimation tasks in various areas of population genetics. Thus, they are potentially well suited to the identification of adaptive introgression. Using simulations, we trained CNNs on genotype matrices derived from genomes sampled from the donor population, the recipient population and a related non-introgressed population, in order to distinguish regions of the genome evolving under adaptive introgression from those evolving neutrally or experiencing selective sweeps. Our CNN architecture exhibits 95% accuracy on simulated data, even when the the genomes are unphased, and accuracy decreases only moderately in the presence of heterosis. As a proof of concept, we applied our trained CNNs to human genomic datasets—both phased and unphased—to detect candidates for adaptive introgression that shaped our evolutionary history.

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Section: Resultsmentioning

confidence: 99%

Detecting adaptive introgression in human evolution using convolutional neural networks

Gower

Picazo

Fumagalli

et al. 2020

Preprint

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“…[25,37] Four pathogenic mutations in the human Cc gene have been identified in families that suffer from mild autosomal dominant thrombocytopenia (THC4; OMIM 612004); a disorder caused by dysregulated platelet formation associated with increased mitochondrial apoptosis. [38][39][40][41] Three of the mutations are missense and give rise to the G41S, Y48H and A51V variants found in the 40-57 Ω-loop, [38][39][40] with the fourth an in-frame deletion that results in a variant whereby Lys100 in the C-terminal α-helix is deleted [41] (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Comparison of the structural dynamic and mitochondrial electron-transfer properties of the proapoptotic human cytochrome c variants, G41S, Y48H and A51V

Deacon

White

Moore

et al. 2020

Journal of Inorganic Biochemistry

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Mitochondrial cytochrome c is associated with electron transfer in the respiratory chain and in apoptosis. Four cytochrome c variants have been identified in families that suffer from mild autosomal dominant thrombocytopenia, a platelet disorder associated with increased apoptosis. Three out of the four substitutions, G41S, Y48H and A51V are located on the 40-57 Ω-loop. The G41S and Y48H variants perturb key physicochemical and dynamic properties that result in enhanced functional features associated with apoptotic activity. Herein we characterise the ferric A51V variant. We show by chemical denaturation that this variant causes the native state to be destabilized. Through azide binding kinetics, the population of a pentacoordinate heme form, whereby the Met80 axial ligand is dissociated, is estimated to be of equal magnitude to that found in the Y48H variant. This pentacoordinate form gives rise to peroxidase activity, which despite the similar pentacoordinate population of the A51V variant to that of the Y48H variant, the peroxidase activity of the A51V variant is supressed. Far-UV circular dichroism spectroscopy and pH jump studies, suggest that a combination of structural and dynamic features in addition to the population of the pentacoordinate form regulate peroxidase activity in these disease variants. Additionally, the steady-state ratio of ferric/ferrous cytochrome c when in turnover with cytochrome c oxidase has been investigated for all 40-57 Ω-loop variants. These studies show that the lower pKa of the alkaline transition for the disease causing variants increases the ferric to ferrous heme ratio, indicating a possible influence on respiration in vivo.

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“…Cytc CYCS/CYC1 paralog CYC7 [197,198] HCCS/CYC3 [199][200][201] In order to use the heterologous complementation approach, the human cDNA is inserted in a specific yeast expression vector, under the control of an appropriate promoter, and containing a yeast selectable marker.…”

Section: Pdss1/coq1mentioning

confidence: 99%

The Power of Yeast in Modelling Human Nuclear Mutations Associated with Mitochondrial Diseases

Berti

Punzio

Dallabona

et al. 2021

Genes

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The increasing application of next generation sequencing approaches to the analysis of human exome and whole genome data has enabled the identification of novel variants and new genes involved in mitochondrial diseases. The ability of surviving in the absence of oxidative phosphorylation (OXPHOS) and mitochondrial genome makes the yeast Saccharomyces cerevisiae an excellent model system for investigating the role of these new variants in mitochondrial-related conditions and dissecting the molecular mechanisms associated with these diseases. The aim of this review was to highlight the main advantages offered by this model for the study of mitochondrial diseases, from the validation and characterisation of novel mutations to the dissection of the role played by genes in mitochondrial functionality and the discovery of potential therapeutic molecules. The review also provides a summary of the main contributions to the understanding of mitochondrial diseases emerged from the study of this simple eukaryotic organism.

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A novel CYCS mutation in the α‐helix of the CYCS C‐terminal domain causes non‐syndromic thrombocytopenia

Cited by 24 publications

References 14 publications

Detecting adaptive introgression in human evolution using convolutional neural networks

Detecting adaptive introgression in human evolution using convolutional neural networks

Comparison of the structural dynamic and mitochondrial electron-transfer properties of the proapoptotic human cytochrome c variants, G41S, Y48H and A51V

The Power of Yeast in Modelling Human Nuclear Mutations Associated with Mitochondrial Diseases

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