C14ORF39/SIX6OS1 is a constituent of the synaptonemal complex and is essential for mouse fertility

Gómez-H, Laura; Felipe‐Medina, Natalia; Sánchez-Martı́n, Manuel; Davies, Owen R.; Ramos, Isabel; García‐Tuñón, Ignacio; Rooij, Dirk G. de; Dereli, Ihsan; Tóth, Attila; Barbero, José Luís; Benavente, Ricardo; Llano, Elena; Pendas, Alberto M.

doi:10.1038/ncomms13298

Cited by 87 publications

(131 citation statements)

References 56 publications

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“…The fertility results herein reported evidence an absence of sexual dimorphism for this CE-related mutation. This would be in accordance with previous observations for mice with loss-of-function of CR components-coding genes, which were equally infertile in both genders [25,29,30,33–35], as opposed to LE-component mutants that showed sexual dimorphism [22, 32].…”

Section: Discussionsupporting

confidence: 93%

“…TF SYCP1 and CE SYCE3), while others would be loaded later ( e.g. CE TEX12) [22,28–30,60–64]. Representative results are shown in Figure 3.…”

Section: Resultsmentioning

confidence: 99%

“…The CE together with the TFs constitute the SC central region (CR). So far, eight different SC protein components have been identified, including LE proteins SYCP3 [19, 20] and SYCP2 [21–23], TF constituent SYCP1 [24–26], and CE components SYCE1, SYCE2, SYCE3, TEX12, and SIX6OS [27–30].…”

Section: Introductionmentioning

confidence: 99%

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Familial primary ovarian insufficiency associated with aSYCE1point mutation: Defective meiosis elucidated in humanized mice

Hernández-López

Geisinger

Trovero

et al. 2020

Preprint

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AbstractObjectiveTo investigate if nonsense mutation SYCE1 c.613C˃T -found in women with familial primary ovarian insufficiency (POI)- is actually responsible for infertility, and to elucidate the involved molecular mechanisms.DesignAs most fundamental mammalian oogenesis events occur during the embryonic phase, thus hindering the study of POI’s etiology/pathogeny in infertile women, we have used CRISPR/Cas9 technology to generate a mouse model line with an equivalent genome alteration (humanized mice).SettingAcademic research laboratories.InterventionsWe present the characterization of the biallelic mutant mice phenotype, compared to wild type and monoallelic littermates.AnimalsStudies were conducted employing the generated humanized mice. All studies were performed for both genders, except otherwise stated.Main outcome measuresreproductive capability by fertility tests; gonadal histological analysis; evaluation of chromosome synapsis and synaptonemal complex (SC) assembly by immunolocalizations; protein studies by Western blotting; transcript quantification by RT-qPCR.ResultsThe studied mutation proved to be the actual cause of the infertile phenotype, both in female and male mice homozygous for the change, confirming infertility of genetic origin with a recessive mode of inheritance. The mechanisms that lead to infertility are related to chromosome synapsis defects; no putative truncated SYCE1 protein was observed, and Syce1 transcript was hardly detected in biallelic mutants.ConclusionsWe present for the first time the generation of humanized mice to study the actual consequences of a SC component mutation found in women with familial POI. By this approach we could confirm the suspected etiology, and shed light on the underlying molecular mechanism.

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Section: Discussionsupporting

confidence: 93%

“…TF SYCP1 and CE SYCE3), while others would be loaded later ( e.g. CE TEX12) [22,28–30,60–64]. Representative results are shown in Figure 3.…”

Section: Resultsmentioning

confidence: 99%

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Familial primary ovarian insufficiency associated with aSYCE1point mutation: Defective meiosis elucidated in humanized mice

Hernández-López

Geisinger

Trovero

et al. 2020

Preprint

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“…interacts with another component of the CE, SIX6OS1. [24,28,29,27,30]. Attempts to analyze distributions of these proteins within the CE using immunogold EM suggested a bilayered organization of the SC central region [31].…”

Section: Introductionmentioning

confidence: 99%

Quantitative basis of meiotic chromosome synapsis analyzed by electron tomography

Spindler

Filbeck

Stigloher

et al. 2019

Preprint

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The synaptonemal complex is a multiprotein complex, which mediates the synapsis and recombination between homologous chromosomes during meiosis. The complex is comprised of two lateral elements and a central element connected by perpendicular transverse filaments (TFs). A 3D model based on actual morphological data of the SC is missing. Here, we applied electron tomography (ET) and manual feature extraction to generate a quantitative 3D model of the murine SC. We quantified the length (90 nm) and width (2 nm) of the TFs.Interestingly, the 80 TFs/µm are distributed asymmetrically in the central region of the SC challenging available models of SC organization. Furthermore, our detailed 3D topological analysis does not support a bilayered organization of the central region as proposed earlier.Overall, our quantitative analysis is relevant to understand the functions and dynamics of the SC and provides the basis for analyzing multiprotein complexes in their morphological context using ET.

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“…It is assumed that the SYNAPTONEMAL COMPLEX CENTRAL ELEMENT PROTEIN 1 LIKE gene ( SYCE1L , GID: GC16P077233) has similar functions to its paralogue SYCE1 (OMIM 611486) (https://www.uniprot.org). SYCE1 is one of the central components of the SC, which is formed by lateral, transverse, and central elements in mammals (Gómez et al ., ). Disruption of Syce1 also leads to infertility in mice due to failure in the SC formation and, consequently, meiosis arrest (Dunne & Davies, ).…”

Section: Discussionmentioning

confidence: 97%

Sequence analysis of 37 candidate genes for male infertility: challenges in variant assessment and validating genes

et al. 2019

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Background The routine genetic analysis for diagnosing male infertility has not changed over the last twenty years, and currently available tests can only determine the etiology of 4% of unselected infertile patients. Thus, to create new diagnostic assays, we must better understand the molecular and genetic mechanisms of male infertility. Although next‐generation sequencing allows for simultaneous analysis of hundreds of genes and the discovery of novel candidates related to male infertility, so far only a few gene candidates have enough sound evidence to support the gene–disease relationship. Objective Since complementary studies are required to validate genes, we aimed to analyze the presence of potentially pathogenic rare variants in a set of candidate genes related to azoospermia in a hitherto understudied South American population. Subjects and Methods We performed whole exome sequencing in a group of 16 patients with non‐obstructive azoospermia from Ribeirão Preto, Brazil. Based on a recent systematic review of monogenic causes of male infertility, we selected a set of 37 genes related to azoospermia, Sertoli‐Cell‐Only histology, and spermatogenic arrest to analyze. The identified variants were confirmed by Sanger sequencing, and their functional consequence was predicted by in silico programs. Results We identified potential pathogenic variants in seven genes in six patients. Two variants, c.671A>G (p.(Asn224Ser)) in DMRT1 and c.91C>T (p.(Arg31Cys)) in REC8, have already been described in association with azoospermia. We also found new variants in genes that already have moderate evidence of being linked to spermatogenic failure (TEX15, KLHL10), in genes with limited evidence (DNMT3B, TEX14) and in one novel promising candidate gene that has no evidence so far (SYCE1L). Discussion Although this study included a small number of patients, the process of rationally selecting genes allowed us to detect rare potentially pathogenic variants, providing supporting evidence for validating candidate genes associated with azoospermia.

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C14ORF39/SIX6OS1 is a constituent of the synaptonemal complex and is essential for mouse fertility

Cited by 87 publications

References 56 publications

Familial primary ovarian insufficiency associated with aSYCE1point mutation: Defective meiosis elucidated in humanized mice

Familial primary ovarian insufficiency associated with aSYCE1point mutation: Defective meiosis elucidated in humanized mice

Quantitative basis of meiotic chromosome synapsis analyzed by electron tomography

Sequence analysis of 37 candidate genes for male infertility: challenges in variant assessment and validating genes

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