PMID- 27094479 OWN - NLM STAT- MEDLINE DCOM- 20180305 LR - 20180407 IS - 1460-2350 (Electronic) IS - 0268-1161 (Linking) VI - 31 IP - 6 DP - 2016 Jun TI - Patients with multiple morphological abnormalities of the sperm flagella due to DNAH1 mutations have a good prognosis following intracytoplasmic sperm injection. PG - 1164-72 LID - 10.1093/humrep/dew083 [doi] AB - STUDY QUESTION: Does DNAH1 status influence intracytoplasmic sperm injection (ICSI) outcomes for patients with multiple morphological abnormalities of the sperm flagella (MMAF)? SUMMARY ANSWER: Despite a highly abnormal morphology, sperm from MMAF patients with DNAH1 mutations have a low aneuploidy rate and good nuclear quality, leading to good embryonic development following ICSI and a high pregnancy rate. WHAT IS KNOWN ALREADY: Teratozoospermia represents a heterogeneous group including a wide range of phenotypes. Among all these qualitative defects, a flagellar phenotype called MMAF is characterized by a mosaic of morphological abnormalities of the flagellum, including coiled, bent, irregular, short or/and absent flagella, mainly due to the absence of the axonemal central pair microtubules. We previously demonstrated that homozygous mutations in the DNAH1 gene, encoding an inner arm heavy chain dynein, are frequently found in patients with MMAF (28% of the patients from the initial cohort). Numerous studies have reported an increased rate of aneuploidy and a poor sperm nuclear quality related to sperm flagellar abnormalities, which could impede ICSI outcome. Moreover, success rates after ICSI may be influenced by the type of ultrastructural flagellar defects and/or by the gene defects carried by the patients. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study included 6 infertile males with MMAF due to deleterious homozygous DNAH1 mutations and their respective spouses, who underwent 9 ISCI cycles, with 16 embryos being transferred. ICSI results were compared with two control populations of 13 MMAF men without DNAH1 mutations and an aged-matched control group of 1431 non-MMAF couples. All ICSI attempts took place between 2000 and 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: Clinical and biological data were collected from patients treated for infertility at the CPSR les Jasmins in Tunis (Tunisia). We compared the ICSI outcomes obtained with couples including DNAH1 mutated and nonmutated patients and non-MMAF couples. For the analysis of the chromosomal status, fluorescence in situ hybridization (FISH) analyses were performed on sperm cells from 3 DNAH1-mutated patients and from 29 fertile control subjects. Sperm chromatin condensation and DNA fragmentation were evaluated using aniline blue staining and TUNEL assays, respectively, on sperm cells from 3 DNAH1-mutated men and 6 fertile controls. MAIN RESULTS AND THE ROLE OF CHANCE: There was a significantly increased proportion of disomy XY and 18 in sperm from DNAH1 mutated patients compared with fertile controls (1.52 versus 0.28%, P = 0.0001 and 0.64 versus 0.09%, P = 0.0001). However, there were no statistically significant differences among sperm from the two groups in their frequencies of either 13, 21, XX or YY disomy or diploidy. Measures of DNA compaction and fragmentation demonstrated a good nuclear sperm quality among DNAH1 mutated men. The overall fertilization, pregnancy and delivery rates of couples including DNAH1 mutated men were of 70.8, 50.0 and 37.5%, respectively. There were no statistically significant differences in any of these parameters compared with the two control groups (P > 0.05). LIMITATIONS, REASONS FOR CAUTION: A limitation of this study is the small number of DNAH1-mutated patients available and the low number of genes identified in MMAF. Further genetic studies are warranted to identify other MMAF-inducing genes to better characterize the genetic etiology of the MMAF phenotype and to improve the management of patients diagnosed with flagellar defects. WIDER IMPLICATIONS OF THE FINDINGS: MMAF patients with DNAH1 mutations have low aneuploidy rates and good nuclear sperm quality, explaining the high pregnancy rate obtained with these patients. Good ICSI results were obtained for both MMAF groups (DNAH1 mutated and nonmutated), suggesting that patients presenting with asthenozoospermia due to flagellar defects have a good ICSI prognosis irrespective of their genotype. The majority of MMAF cases currently remain idiopathic with no genetic cause yet identified. In depth genetic analysis of these patients using next generation sequencing should reveal new causal genes. Subsequent genotype phenotype analyses could improve advice and care provided to MMAF patients. STUDY FUNDING/COMPETING INTERESTS: 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) and the MAS-Flagella project, financed by the French ANR and the Direction Generale de l'Offre de Soins (DGOS). CI - (c) The Author 2016. 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. FAU - Wambergue, Clementine AU - Wambergue C AD - Universite Grenoble Alpes, Grenoble F-38000, France Equipe 'Genetics Epigenetics and Therapies of Infertility', Institut Albert Bonniot (IAB), INSERM U1209, CNRS UMR 5309, Grenoble F-38000, France CHU de Grenoble, UF de Genetique Chromosomique, Grenoble F-38000, France. FAU - Zouari, Raoudha AU - Zouari R AD - Polyclinique les Jasmins, Centre d'Aide Medicale a la Procreation, Centre Urbain Nord, 1003 Tunis, Tunisia. FAU - Fourati Ben Mustapha, Selima AU - Fourati Ben Mustapha S AD - Polyclinique les Jasmins, Centre d'Aide Medicale a la Procreation, Centre Urbain Nord, 1003 Tunis, Tunisia. FAU - Martinez, Guillaume AU - Martinez G AD - Universite Grenoble Alpes, Grenoble F-38000, France Equipe 'Genetics Epigenetics and Therapies of Infertility', Institut Albert Bonniot (IAB), INSERM U1209, CNRS UMR 5309, Grenoble F-38000, France CHU de Grenoble, UF de Biologie de la procreation, Grenoble F-38000, France. FAU - Devillard, Francoise AU - Devillard F AD - CHU de Grenoble, UF de Genetique Chromosomique, Grenoble F-38000, France. FAU - Hennebicq, Sylviane AU - Hennebicq S AD - Universite Grenoble Alpes, Grenoble F-38000, France Equipe 'Genetics Epigenetics and Therapies of Infertility', Institut Albert Bonniot (IAB), INSERM U1209, CNRS UMR 5309, Grenoble F-38000, France CHU de Grenoble, UF de Biologie de la procreation, Grenoble F-38000, France. FAU - Satre, Veronique AU - Satre V AD - Universite Grenoble Alpes, Grenoble F-38000, France Equipe 'Genetics Epigenetics and Therapies of Infertility', Institut Albert Bonniot (IAB), INSERM U1209, CNRS UMR 5309, Grenoble F-38000, France CHU de Grenoble, UF de Genetique Chromosomique, Grenoble F-38000, France. FAU - Brouillet, Sophie AU - Brouillet S AD - Universite Grenoble Alpes, Grenoble F-38000, France CHU de Grenoble, UF de Biologie de la procreation, Grenoble F-38000, France. FAU - Halouani, Lazhar AU - Halouani L AD - Polyclinique les Jasmins, Centre d'Aide Medicale a la Procreation, Centre Urbain Nord, 1003 Tunis, Tunisia. FAU - Marrakchi, Ouafi AU - Marrakchi O AD - Polyclinique les Jasmins, Centre d'Aide Medicale a la Procreation, Centre Urbain Nord, 1003 Tunis, Tunisia. FAU - Makni, Mounir AU - Makni M AD - Polyclinique les Jasmins, Centre d'Aide Medicale a la Procreation, Centre Urbain Nord, 1003 Tunis, Tunisia. FAU - Latrous, Habib AU - Latrous H AD - Polyclinique les Jasmins, Centre d'Aide Medicale a la Procreation, Centre Urbain Nord, 1003 Tunis, Tunisia. FAU - Kharouf, Mahmoud AU - Kharouf M AD - Polyclinique les Jasmins, Centre d'Aide Medicale a la Procreation, Centre Urbain Nord, 1003 Tunis, Tunisia. FAU - Amblard, Florence AU - Amblard F AD - CHU de Grenoble, UF de Genetique Chromosomique, Grenoble F-38000, France. FAU - Arnoult, Christophe AU - Arnoult C AD - Universite Grenoble Alpes, Grenoble F-38000, France Equipe 'Genetics Epigenetics and Therapies of Infertility', Institut Albert Bonniot (IAB), INSERM U1209, CNRS UMR 5309, Grenoble F-38000, France. FAU - Ray, Pierre F AU - Ray PF AD - Universite Grenoble Alpes, Grenoble F-38000, France Equipe 'Genetics Epigenetics and Therapies of Infertility', Institut Albert Bonniot (IAB), INSERM U1209, CNRS UMR 5309, Grenoble F-38000, France CHU de Grenoble, UF de Biochimie Genetique et Moleculaire, Grenoble F-38000, France pray@chu-grenoble.fr. FAU - Coutton, Charles AU - Coutton C AD - Universite Grenoble Alpes, Grenoble F-38000, France Equipe 'Genetics Epigenetics and Therapies of Infertility', Institut Albert Bonniot (IAB), INSERM U1209, CNRS UMR 5309, Grenoble F-38000, France CHU de Grenoble, UF de Genetique Chromosomique, Grenoble F-38000, France. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160419 PL - England TA - Hum Reprod JT - Human reproduction (Oxford, England) JID - 8701199 RN - EC 3.6.4.2 (DNAH1 protein, human) RN - EC 3.6.4.2 (Dyneins) SB - IM CIN - J Urol. 2017 Mar;197(3 Pt 1):786. PMID: 28208560 MH - Adult MH - Axoneme/*genetics/ultrastructure MH - DNA Fragmentation MH - Dyneins/*genetics MH - Female MH - Flagella/ultrastructure MH - Humans MH - In Situ Hybridization, Fluorescence MH - In Situ Nick-End Labeling MH - Infertility, Male/*genetics/therapy MH - Male MH - *Mutation MH - Oocyte Retrieval MH - Ovulation Induction MH - Pregnancy MH - Pregnancy Rate MH - Prognosis MH - Retrospective Studies MH - *Sperm Injections, Intracytoplasmic MH - Spermatozoa/*abnormalities MH - Treatment Outcome OTO - NOTNLM OT - DNAH1 OT - FISH OT - ICSI OT - MMAF OT - flagellum OT - genetics OT - male infertility OT - teratozoospermia EDAT- 2016/04/21 06:00 MHDA- 2018/03/06 06:00 CRDT- 2016/04/21 06:00 PHST- 2015/11/26 00:00 [received] PHST- 2016/03/23 00:00 [accepted] PHST- 2016/04/21 06:00 [entrez] PHST- 2016/04/21 06:00 [pubmed] PHST- 2018/03/06 06:00 [medline] AID - dew083 [pii] AID - 10.1093/humrep/dew083 [doi] PST - ppublish SO - Hum Reprod. 2016 Jun;31(6):1164-72. doi: 10.1093/humrep/dew083. Epub 2016 Apr 19.