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Coutton C.,French National Center for Scientific Research | Coutton C.,Joseph Fourier University | Coutton C.,Grenoble University Hospital Center | Zouari R.,Clinique de la Reproduction les Jasmins | And 32 more authors.
Human Reproduction | Year: 2012

summary answer: Two DPY19L2 heterozygous deletions and three point mutations were identified, thus further confirming that genetic alterations of the DPY19L2 gene are the main cause of globozoospermia and indicating that DPY19L2 molecular diagnostics should not be stopped in the absence of a homozygous gene deletion. what is known already: Globozoospermia is a rare phenotype of primary male infertility characterized by the production of a majority of round-headed spermatozoa without acrosome.We demonstrated previously that most cases in man were caused by a recurrent homozygous deletion of the totality of the DPY19L2 gene, preventing sperm head elongation and acrosome formation. In mammals, DPY19L2 has three paralogs of yet unknown function and one highly homologous pseudogene showing .95% sequence identity with DPY19L2. Specific amplification and sequencing of DPY19L2 have so far been hampered by the presence of this pseudogene which has greatly complicated specific amplification and sequencing. study design, size, duration: In this cohort study, 34 patients presenting with globozoospermia were recruited during routine infertility treatment in infertility centers in France and Tunisia between January 2008 and December 2011. The molecular variants identified in patients were screened in 200 individuals from the general population to exclude frequent non-pathological polymorphisms. participants/materials, setting, methods: We developed a Multiplex Ligation-dependent Probe Amplification test to detect the presence of heterozygous deletions and identified the conditions to specifically amplify and sequence the 22 exons and intronic boundaries of the DPY19L2 gene. The pathogenicity of the identified mutations and their action on the protein were evaluated in silico. main results and the role of chance: There were 23 patients who were homozygous for the DPY19L2 deletion (67.6%). Only eight of the eleven non-homozygously deleted patients could be sequenced due to poor DNA quality of three patients. Two patients were compound heterozygous carrying one DPY19L2 deleted allele associated respectively with a nonsense (p.Q342) and a missense mutation (p.R290H). One patient was homozygous for p.M358K, another missense mutation affecting a highly conserved amino acid. Due to & The Author 2012. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com Human Reproduction, Vol.27, No.8 pp. 2549-2558, 2012 Advanced Access publication on May 24, 2012 doi:10.1093/humrep/des160 Downloaded from http://humrep.oxfordjournals.org/ at SCOPUS EFLOWI on November 23, 2012 the localization of this mutation and the physicochemical properties of the substituted amino acids, we believe that this variant is likely to disrupt one of the protein transmembrane domains and destabilize the protein. Overall, 84% of the fully analysed patients (n = 31) had a molecular alteration of DPY19L2. There was no clear phenotypic difference between the homozygous deleted individual, patients carrying a point mutation and undiagnosed patients. limitations, reasons for caution: Globally poor fertilization rates are observed after intracytoplasmic sperm injection of round spermatozoa. Further work is needed to assess whether DPY19L2 mutated patients present a better or worse prognostic than the non-diagnosed patients. Evaluation of the potential benefit of treatment with a calcium ionophore, described to improve fertilization, should be evaluated in these two groups. wider implications of the findings: In previous work, deletions of DPY19L2 had only been identified in North African patients. Here we have identified DPY19L2 deletions and point mutations in European patients, indicating that globozoospemia caused by a molecular defect of DPY19L2 can be expected in individuals from any ethnic background. study funding/competing interest(s): None of the authors have any competing interest. This work is part of the project 'Identification and Characterization of Genes Involved in Infertility (ICG2I)' funded by the program GENOPAT 2009 from the French Research Agency (ANR). © The Author 2012. Source

Mitchell V.,EA 4308 Gametogenese et qualite du gamete | Mitchell V.,Institute Of Biologie Of La Reproduction Spermiologie Cecos | Sigala J.,EA 4308 Gametogenese et qualite du gamete | Sigala J.,Institute Of Biologie Of La Reproduction Spermiologie Cecos | And 10 more authors.
Andrologia | Year: 2015

Although electron microscopy provides a detailed analysis of ultrastructural abnormalities, this technique is not available in all laboratories. We sought to determine whether certain characteristics of the flagellum as assessed by light microscopy were related to axonemal abnormalities. Forty-one patients with an absence of outer dynein arms (type I), a lack of a central complex (type III) and an absence of peripheral doublets (type IV) were studied. Sperm morphology was scored according to David's modified classification. Flagella with an irregular thickness were classified as being of normal length, short or broken. There were correlations between missing outer dynein arms and abnormal, short or coiled flagellum. Type III patients showed the highest flagellar defects (a short (P = 0.0027) or an absent flagellum (P = 0.011)). Just over 68% of the irregular flagella were short in Type III patients, whereas this value was only 34.5% in type I and 26.4% in type IV (P = 0.002). There was a negative correlation between misassembly and spermatozoa of irregular flagella (r = -0.79; P = 0.019). It is concluded that light microscopy analysis of flagellum abnormalities may help provide a correct diagnosis, identify sperm abnormalities with fertility potentials and outcomes in assisted reproduction technologies and assess the genetic risk. © 2014 Blackwell Verlag GmbH. Source

Rondanino C.,EA 4308 Gametogenese et qualite du gamete | Rondanino C.,University of Rouen | Duchesne V.,EA 4308 Gametogenese et qualite du gamete | Duchesne V.,University of Rouen | And 10 more authors.
Reproductive BioMedicine Online | Year: 2015

Abstract The decapitated sperm defect is a rare type of teratozoospermia responsible for male infertility. Spermatozoa from patients affected by this syndrome are used for intracytoplasmic sperm injection (ICSI) although little is known about their DNA integrity. This study evaluated sperm nuclear alterations in four patients and ten fertile men (control group). Sperm samples were examined by light, transmission electron and high-magnification contrast microscopy and analysed after terminal deoxynucleotidyltransferase-mediated dUTP nick end labelling, aniline blue staining and fluorescence in-situ hybridization. Spermatozoa from patients presented varying degrees of decapitation, along with morphological and ultrastructural head abnormalities. Whereas the proportion of spermatozoa with fragmented DNA and numerical chromosome abnormalities was similar in patients 1-3 and controls, the percentage of spermatozoa with hypocondensed chromatin was higher in patients 1-3 than in fertile men. Patient 4 presented a distinct phenotype, with an increased proportion of flagellated spermatozoa with DNA strand breaks as well as increased aneuploidy and diploidy rates compared with controls and with patients 1-3. No successful pregnancy resulted from ICSI although embryos were obtained for three patients. The morphological defects and the nuclear alterations observed in spermatozoa of patients with the decapitated sperm syndrome may have contributed to ICSI failures. © 2015 Reproductive Healthcare Ltd. Source

Mitchell V.,EA4308 gametogenese et qualite du gamete | Mitchell V.,Institute Of Biologie Of La Reproduction Spermiologie Cecos | Sigala J.,Institute Of Biologie Of La Reproduction Spermiologie Cecos | Jumeau F.,EA4308 gametogenese et qualite du gamete | And 7 more authors.
Gynecologie Obstetrique Fertilite | Year: 2012

In the management of asthenozoospermia, the spermogram-spermocytogram plays an important role during diagnosis. It is of major importance to distinguish between necrozoospermia and sperm vitality. An ultrastructural study of spermatozoa is processed in the case of primary infertility without female implication, severe, unexplained and irreversible asthenozoospermia, sperm vitality at least 50 % and normal concentration of spermatozoa. Ultrastructural flagellar abnormalities are numerous and involve most spermatozoa. ICSI provides a suitable solution for patients with sperm flagellar defects to conceive children with their own gametes but the rate of ICSI success may be influenced by the type of flagellar abnormality. Some fertilization and birth rate failures which are related to some flagellar abnormalities might occur. © 2012 Elsevier Masson SAS. All rights reserved. Source

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