Bi-allelic DNAH8 Variants Lead to Multiple Morphological Abnormalities of the Sperm Flagella and Primary Male Infertility.

Abnormalities, Multiple / genetics Alleles Animals Axonemal Dyneins / genetics Cohort Studies Exome / genetics Female Flagella / genetics Genetic Variation / genetics Homozygote Humans Infertility, Male / genetics Male Mice Mice, Knockout Sperm Tail / pathology Spermatozoa / abnormalities Testis / abnormalities Exome Sequencing / methods

CRISPR DNAH17 DNAH8 ICSI dynein exome flagella infertility knockout sperm

Journal

American journal of human genetics

ISSN: 1537-6605

Titre abrégé: Am J Hum Genet

Pays: United States

ID NLM: 0370475

Informations de publication

Date de publication:
06 08 2020

Historique:

received: 19 03 2020

accepted: 05 06 2020

pubmed: 4 7 2020

medline: 21 10 2020

entrez: 4 7 2020

Statut: ppublish

Résumé

Sperm malformation is a direct factor for male infertility. Multiple morphological abnormalities of the flagella (MMAF), a severe form of asthenoteratozoospermia, are characterized by immotile spermatozoa with malformed and/or absent flagella in the ejaculate. Previous studies indicated genetic heterogeneity in MMAF. To further define genetic factors underlying MMAF, we performed whole-exome sequencing in a cohort of 90 Chinese MMAF-affected men. Two cases (2.2%) were identified as carrying bi-allelic missense DNAH8 variants, variants which were either absent or rare in the control human population and were predicted to be deleterious by multiple bioinformatic tools. Re-analysis of exome data from a second cohort of 167 MMAF-affected men from France, Iran, and North Africa permitted the identification of an additional male carrying a DNAH8 homozygous frameshift variant. DNAH8 encodes a dynein axonemal heavy-chain component that is expressed preferentially in the testis. Hematoxylin-eosin staining and electron microscopy analyses of the spermatozoa from men harboring bi-allelic DNAH8 variants showed a highly aberrant morphology and ultrastructure of the sperm flagella. Immunofluorescence assays performed on the spermatozoa from men harboring bi-allelic DNAH8 variants revealed the absent or markedly reduced staining of DNAH8 and its associated protein DNAH17. Dnah8-knockout male mice also presented typical MMAF phenotypes and sterility. Interestingly, intracytoplasmic sperm injections using the spermatozoa from Dnah8-knockout male mice resulted in good pregnancy outcomes. Collectively, our experimental observations from humans and mice demonstrate that DNAH8 is essential for sperm flagellar formation and that bi-allelic deleterious DNAH8 variants lead to male infertility with MMAF.

Identifiants

DOI: 10.1016/j.ajhg.2020.06.004 PMID: 32619401 PMC: PMC7413861

pubmed: 32619401

pii: S0002-9297(20)30192-0

doi: 10.1016/j.ajhg.2020.06.004

pmc: PMC7413861

pii:

doi:

Substances chimiques

Dnah8 protein, mouse 0

Axonemal Dyneins EC 3.6.4.2

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

330-341

Subventions

Organisme : NICHD NIH HHS

ID : P01 HD087157

Pays : United States

Organisme : NICHD NIH HHS

ID : R01 HD088412

Pays : United States

Informations de copyright

Références

Annu Rev Physiol. 2007;69:423-50

pubmed: 17059358

Mol Biol Cell. 1998 Sep;9(9):2337-47

pubmed: 9725897

Am J Hum Genet. 2019 Apr 4;104(4):738-748

pubmed: 30929735

Sci Rep. 2019 Apr 30;9(1):6683

pubmed: 31040315

J Cell Biol. 2010 May 31;189(5):783-94

pubmed: 20513765

Mol Biol Cell. 2013 Dec;24(23):3689-96

pubmed: 24088566

Mol Cell Proteomics. 2013 Feb;12(2):330-42

pubmed: 23161514

J Exp Med. 2020 Feb 3;217(2):

pubmed: 31658987

Nat Rev Mol Cell Biol. 2017 Sep;18(9):533-547

pubmed: 28698599

Asian J Androl. 2020 Nov-Dec;22(6):608-615

pubmed: 32167074

Gene. 2017 Oct 30;633:48-53

pubmed: 28866084

Am J Hum Genet. 2018 Apr 5;102(4):636-648

pubmed: 29606301

Am J Hum Genet. 2019 Feb 7;104(2):331-340

pubmed: 30686508

Am J Respir Crit Care Med. 2005 Jun 15;171(12):1343-9

pubmed: 15750039

Hum Reprod Update. 2010 May-Jun;16(3):231-45

pubmed: 19934213

Am J Hum Genet. 2019 Dec 5;105(6):1148-1167

pubmed: 31735292

Hum Reprod. 2005 Oct;20(10):2790-4

pubmed: 15980003

J Proteomics. 2013 Feb 21;79:114-22

pubmed: 23268119

Cytoskeleton (Hoboken). 2015 Jan;72(1):16-28

pubmed: 25558044

Hum Reprod. 2016 Jan;31(1):10-23

pubmed: 26472152

J Med Genet. 2006 Jan;43(1):62-73

pubmed: 15937072

Am J Hum Genet. 2019 Jul 3;105(1):198-212

pubmed: 31178125

Hum Mol Genet. 2003 Apr 1;12 Spec No 1:R27-35

pubmed: 12668594

Am J Hum Genet. 2018 Dec 6;103(6):984-994

pubmed: 30471717

Cold Spring Harb Perspect Biol. 2016 Nov 1;8(11):

pubmed: 27527589

Am J Respir Cell Mol Biol. 2016 Aug;55(2):213-24

pubmed: 26909801

Am J Hum Genet. 2001 Apr;68(4):1030-5

pubmed: 11231901

Am J Hum Genet. 2019 Dec 5;105(6):1168-1181

pubmed: 31735294

Am J Hum Genet. 2018 Dec 6;103(6):995-1008

pubmed: 30471718

Am J Hum Genet. 2017 Jun 1;100(6):854-864

pubmed: 28552195

Dev Biol. 2005 Sep 1;285(1):57-69

pubmed: 16054618

Cold Spring Harb Perspect Biol. 2017 Jan 3;9(1):

pubmed: 27601632

Nat Commun. 2018 Feb 15;9(1):686

pubmed: 29449551

J Cell Biol. 2012 Jun 25;197(7):857-67

pubmed: 22733998

Biochim Biophys Acta. 2013 Jun-Jul;1829(6-7):487-90

pubmed: 23583720

Fertil Steril. 2014 Apr;101(4):945-9

pubmed: 24524830

Am J Hum Genet. 2018 Sep 6;103(3):413-420

pubmed: 30122541

Am J Hum Genet. 2008 Nov;83(5):547-58

pubmed: 18950741

Hum Reprod. 2016 Jun;31(6):1164-72

pubmed: 27094479

Cold Spring Harb Perspect Biol. 2017 Aug 1;9(8):

pubmed: 28765157

Asian J Androl. 2012 Jan;14(1):14-23

pubmed: 22198630

Hum Genet. 2020 Jan 16;:

pubmed: 31950240

Am J Hum Genet. 2014 Jan 2;94(1):95-104

pubmed: 24360805

Am J Hum Genet. 2018 Sep 6;103(3):400-412

pubmed: 30122540

J Diet Suppl. 2019;16(2):245-256

pubmed: 29451828

Hum Reprod. 2019 Oct 2;34(10):2071-2079

pubmed: 31621862

Mol Biol Cell. 2015 Oct 15;26(20):3596-605

pubmed: 26310446