October 2018
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305 Reads
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October 2018
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305 Reads
September 2018
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6 Reads
August 2018
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1,033 Reads
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112 Citations
Human Reproduction
Study question: Can whole-exome sequencing (WES) of infertile patients identify new genes responsible for multiple morphological abnormalities of the sperm flagella (MMAF)? Summary answer: WES analysis of 78 infertile men with a MMAF phenotype permitted the identification of four homozygous mutations in the fibrous sheath (FS) interacting protein 2 (FSIP2) gene in four unrelated individuals. What is known already: The use of high-throughput sequencing techniques revealed that mutations in the dynein axonemal heavy chain 1 (DNAH1) gene, and in the cilia and flagella associated protein 43 (CFAP43) and 44 (CFAP44) genes account for approximately one-third of MMAF cases thus indicating that other relevant genes await identification. Study design, size, duration: This was a retrospective genetics study of 78 patients presenting a MMAF phenotype who were recruited in three fertility clinics between 2008 and 2015. Control sperm samples were obtained from normospermic donors. Allelic frequency for control subjects was derived from large public databases. Participants/materials, setting, methods: WES was performed for all 78 subjects. All identified variants were confirmed by Sanger sequencing. Relative mRNA expression levels for the selected candidate gene (FSIP2) was assessed by quantitative RT-PCR in a panel of normal human and mouse tissues. To characterize the structural and ultrastructural anomalies present in patients' sperm, immunofluorescence (IF) was performed on sperm samples from two subjects with a mutation and one control and transmission electron microscopy (TEM) analyses was performed on sperm samples from one subject with a mutation and one control. Main results and the role of chance: We identified four unrelated patients (4/78, 5.1%) with homozygous loss of function mutations in the FSIP2 gene, which encodes a protein of the sperm FS and is specifically expressed in human and mouse testis. None of these mutations were reported in control sequence databases. TEM analyses showed a complete disorganization of the FS associated with axonemal defects. IF analyses confirmed that the central-pair microtubules and the inner and outer dynein arms of the axoneme were abnormal in all four patients carrying FSIP2 mutations. Importantly, and in contrast to what was observed in patients with MMAF and mutations in other MMAF-related genes (DNAH1, CFAP43 and CFAP44), mutations in FSIP2 led to the absence of A-kinase anchoring protein 4 (AKAP4). Limitations, reasons for caution: The low number of biological samples and the absence of a reliable anti-FSIP2 antibody prevented the formal demonstration that the FSIP2 protein was absent in sperm from subjects with a FSIP2 mutation. Wider implications of the findings: Our findings indicate that FSIP2 is one of the main genes involved in MMAF syndrome. In humans, genes previously associated with a MMAF phenotype encoded axonemal-associated proteins (DNAH1, CFAP43 and CFAP44). We show here that FSIP2, a protein of the sperm FS, is also logically associated with MMAF syndrome as we showed that it is necessary for FS assembly and for the overall axonemal and flagellar biogenesis. As was suggested before in mouse and man, our results also suggest that defects in AKAP4, one of the main proteins interacting with FSIP2, would induce a MMAF phenotype. Finally, this work reinforces the demonstration that WES sequencing is a good strategy to reach a genetic diagnosis for patients with severe male infertility phenotypes. Study funding/competing interest(s): This work was supported by the following grants: the 'MAS-Flagella' project financed by the French ANR and the DGOS for the program PRTS 2014 (14-CE15) and the 'Whole genome sequencing of patients with Flagellar Growth Defects (FGD)' project financed by the Fondation Maladies Rares for the program Séquençage à haut débit 2012. The authors have no conflict of interest.
August 2018
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7 Reads
August 2018
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4 Reads
August 2018
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229 Reads
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97 Citations
The American Journal of Human Genetics
Multiple morphological abnormalities of the sperm flagellum (MMAF) is a severe form of male infertility defined by the presence of a mosaic of anomalies, including short, bent, curled, thick, or absent flagella, resulting from a severe disorganization of the axoneme and of the peri-axonemal structures. Mutations in DNAH1, CFAP43, and CFAP44, three genes encoding axoneme-related proteins, have been described to account for approximately 30% of the MMAF cases reported so far. Here, we searched for pathological copy-number variants in whole-exome sequencing data from a cohort of 78 MMAF-affected subjects to identify additional genes associated with MMAF. In 7 of 78 affected individuals, we identified a homozygous deletion that removes the two penultimate exons of WDR66 (also named CFAP251), a gene coding for an axonemal protein preferentially localized in the testis and described to localize to the calmodulin- and spoke-associated complex at the base of radial spoke 3. Sequence analysis of the breakpoint region revealed in all deleted subjects the presence of a single chimeric SVA (SINE-VNTR-Alu) at the breakpoint site, suggesting that the initial deletion event was potentially mediated by an SVA insertion-recombination mechanism. Study of Trypanosoma WDR66's ortholog (TbWDR66) highlighted high sequence and structural analogy with the human protein and confirmed axonemal localization of the protein. Reproduction of the human deletion in TbWDR66 impaired flagellar movement, thus confirming WDR66 as a gene associated with the MMAF phenotype and highlighting the importance of the WDR66 C-terminal region.
May 2018
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19 Reads
May 2018
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14 Reads
May 2018
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11 Reads
May 2018
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9 Reads
... In the present study, nineteen novel variants of FSIP2 and SPEF2 were identified in eleven patients with MMAF. Previous studies have reported that the frequency of biallelic FSIP2 mutations to be 2.9% (3/105) in patients with oligoasthenozoospermia [17], 5% (2/40) in Chinese men with MMAF [18], and 5.1% (4/78) in North African patients exhibiting the typical MMAF phenotype [19]. Our findings revealed a higher prevalence of FSIP2 variants (8.5%), with loss-of-function (LOF) variants accounting for 3.8% (4/106) and missense variants representing 4.7% (5/106) of cases. ...
August 2018
Human Reproduction
... WDR12 homozygous mutation in men led to tapered-head spermatozoa [15]. In addition, the cilia-and flagella-associated protein 43 (CFAP43, also known as WDR96), CFAP44 (WDR52), CFAP251 (WDR66) and WDR63 proteins are thought to be related to the formation of sperm flagella, and deficiency of these genes in humans and mice can cause multiple morphological abnormalities of sperm flagella (MMAF) and male infertility [16][17][18][19][20]. Recently, our group has explored the function of WDR proteins in spermatogenesis. ...
August 2018
The American Journal of Human Genetics
... Notably, PATL2 encodes an RNA-binding protein that was initially identified as a translational repressor in Xenopus oocytes [29,30], and the overexpression of PATL2 ortholog (labeled P100) represses mRNA translation and blocks oocyte meiosis I progression [30]. PATL2 loss-of-function mutations in humans lead to GV and MI arrest [22], but PATL2 knockout mice exhibit mild OMD phenotypes, mainly exhibiting early embryo arrest phenotype [31,32]. The Patl2-null mouse model revealed that PATL2 mainly functions as an adaptor protein to recruit EIF4E and CPEB1 to maintain the mRNA stability and maternal transcripts dosage in growing oocytes [31]. ...
April 2018
EMBO Molecular Medicine
... The CA plays a critical role in the development and regulation of motile cilia. Mutations in at least 11 CA-associated genes have been reported to cause motile ciliopathies, such as multiple morphological abnormalities of the sperm flagella (MMAF) and primary ciliary dyskinesia (PCD) [4][5][6][7][8][9][10][11][12][13][14]. PCD is a genetically and clinically heterogeneous disease, with an estimated global prevalence of approximately 1:10,000 [15], presenting with various combinations of symptoms including neonatal respiratory distress, persistent wet cough, recurrent and chronic upper and lower respiratory tract infections, bronchiectasis, otitis media with effusion, situs inversus or heterotaxy, hydrocephalus, and infertility [16]. ...
March 2018
The American Journal of Human Genetics
... The flagellated protist Trypanosoma brucei is well known for causing sleeping sickness in Africa. In recent years, it has also emerged as a potent model organism to study cilia and flagella bringing useful insights to the comprehension of several ciliopathies [7][8][9] . Trypanosomes are fascinating organisms to study since they contain a mixture of universal features but also of unique characteristics, presumably linked to their divergent position in the eukaryotic phylogeny. ...
February 2018
... To investigate possible infertility-related genes at common breakpoints on each chromosome and the relationship between these breakpoints and the type of infertility (pregestational or gestational), the data obtained from patients' records were compared with the literature, the results of which are shown in Table 7 Kueng et al. 1997;Maruoka et al. 1998;Ou et al. 1999;Abusheikha et al. 2001;Crackower et al. 1979;Kirby et al. 2004;Reynolds et al. 2005;Galan et al. 2006;Choi et al. 2007;Dieterich et al. 2007;Perera et al. 2007;Sc et al. 2007;Lamarca et al. 2007;Singh et al. 2008Singh et al. , 2019Li et al. 2009Li et al. , 2011Li et al. , 2022Wyatt et al. 2010;Nagai et al. 2011;Saadi et al. 2011;Zheng et al. 2012Zheng et al. , 2020Buchold and Eddy 2012;Heaydaryan et al. 2013;Hodžić et al. 2013;de Mateo and Sassone-Corsi 2014;Purandhar et al. 2014;Devi et al. 2015;Guan et al. 2015;Kwon et al. 2015;Li et al. 2012;Mateusz Kurzawski et al. 2015;Mobasheri et al. 2015;Wang et al. 2015Wang et al. , 2023Tsatsanis et al. 2015;Chirn et al. 2015;Aydos et al. 2016;Marques et al. 2016;Cai et al. 2017;Ghasemi et al. 2017;Kherraf et al. 2017;Sha et al. 2017;Regions and Genes 2018;An et al. 2018;Beurois et al. 2019;Giebler et al. 2019;Qiu et al. 2019;Yoshitaka Fujiharaa et al. 2019;Musio 2020;Liudkovska and Dziembowski 2021;Pantos et al. 2021;Sabetian et al. 2021;Tu et al. 2021;Yuan et al. 2021;Du et al. 2021;Wu et al. 2021;zur Lage P, et al. 2021zur Lage P, et al. . 2021Dong et al. 2022;Jones and Naylor 2022;Woodhouse et al. 2022;Amaral 2022;Baker et al. 2022;Akram et al. 2023;Greither et al. 2023;Gusmano et al. 2023). ...
May 2017
EMBO Molecular Medicine
... In a 2014 report by the FORGE (Finding of Rare Disease Genes) Canada Consortium, WES was only successful in identifying genes in 45% of sporadic cases and 43% of recessive diseases in non-consanguineous families. WGS, where both coding and non-coding regions are sequenced, has several advantages over WES, as it generates a higher level of resolution [105], information on copy number variants (CNVs) [106,107], and epigenomic information [108]. The limited number of recent male factor infertility studies utilizing WGS that have been published are primarily case reports or studies with small cohorts [109][110][111][112][113][114][115][116]. ...
October 2016
Human Reproduction
... It is clear that a sperm might have genetic defects that result in subsequent failure of the fertilization process, which could affect embryonic development. Over the years, studies on PLCζ have formed the basis by which we understand the correlation between oocyte activation and the spermatic factor PLCζ, coded by the PLCZ1 gene [40]. ...
December 2015
Human Molecular Genetics
... X is abundantly expressed in sperm acrosomes, is secreted from activated spermatozoa during acrosome reaction, and hydrolyzes sperm membrane phospholipids to release DHA and DPA as well as LPC.24,69 Pla2g10 −/− spermatozoa show impairment of the late phase of the progesterone-induced acrosome reaction,70 and the reduced ability of Pla2g10 −/− sperm to fertilize oocytes is rescued by supplementation with DPA or LPC during in vitro fertilization.24,69 Hereafter, we focus mainly on the established immune-related roles of sPLA 2 -X in specific tissues where this enzyme is substantially expressed, while the controversial functions reported in other tissues with little or no sPLA 2 -X expression are briefly summarized at the end of this section. ...
December 2015
Journal of Biological Chemistry
... Кодируемый белок экспрессируется в ходе спермиогенеза и остается в зрелых сперматозоидах. В течение сперматогенеза белок SUN5 находится в составе ядерной оболочки, однако в зрелых сперматозоидах локализован в имплантационной ямке HTCA [37]. ...
March 2015