title: Mutations in DNAH1, which encodes an inner arm heavy chain dynein, lead to male infertility from multiple morphological abnormalities of the sperm flagella.
abstract: Ten to fifteen percent of couples are confronted with infertility and a male factor is involved in approximately half the cases. A genetic etiology is likely in most cases yet only few genes have been formally correlated with male infertility. Homozygosity mapping was carried out on a cohort of 20 North African individuals, including 18 index cases, presenting with primary infertility resulting from impaired sperm motility caused by a mosaic of multiple morphological abnormalities of the flagella (MMAF) including absent, short, coiled, bent, and irregular flagella. Five unrelated subjects out of 18 (28%) carried a homozygous variant in DNAH1, which encodes an inner dynein heavy chain and is expressed in testis. RT-PCR, immunostaining, and electronic microscopy were carried out on samples from one of the subjects with a mutation located on a donor splice site. Neither the transcript nor the protein was observed in this individual, confirming the pathogenicity of this variant. A general axonemal disorganization including mislocalization of the microtubule doublets and loss of the inner dynein arms was observed. Although DNAH1 is also expressed in other ciliated cells, infertility was the only symptom of primary ciliary dyskinesia observed in affected subjects, suggesting that DNAH1 function in cilium is not as critical as in sperm flagellum.
authors.affiliation: Université Joseph Fourier, Grenoble 38000, France; Laboratoire AGIM, CNRS FRE3405, Equipe "Andrologie et Génétique," La Tronche 38700, France; Laboratoire de génomique Biomédicale et Oncogénétique, Institut Pasteur de Tunis, 1002 Tunis, Tunisie.
authors.forename: Mariem
authors.initials: M
authors.lastname: Ben Khelifa
authors.affiliation: Université Joseph Fourier, Grenoble 38000, France; Laboratoire AGIM, CNRS FRE3405, Equipe "Andrologie et Génétique," La Tronche 38700, France; CHU de Grenoble, Hôpital Couple Enfant, Département de Génétique et Procréation, Laboratoire de Génétique Chromosomique, Grenoble 38000, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Coutton
authors.affiliation: Clinique des Jasmins, 23, Av. Louis BRAILLE, 1002 Tunis, Tunisia.
authors.forename: Raoudha
authors.initials: R
authors.lastname: Zouari
authors.affiliation: Université Joseph Fourier, Grenoble 38000, France; Laboratoire AGIM, CNRS FRE3405, Equipe "Andrologie et Génétique," La Tronche 38700, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Karaouzène
authors.affiliation: Université Joseph Fourier, Grenoble 38000, France; CHU de Grenoble, Institut de Biologie et Pathologie, Département de Biochimie, Toxicologie et Pharmacologie (DBTP), UF de Biochimie et Génétique Moléculaire, Grenoble 38000, France; INSERM, U836, Grenoble Institute of Neuroscience, La Tronche 38700, France.
authors.forename: John
authors.initials: J
authors.lastname: Rendu
authors.affiliation: Université Joseph Fourier, Grenoble 38000, France; INSERM, U836, Grenoble Institute of Neuroscience, La Tronche 38700, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Bidart
authors.affiliation: Université Joseph Fourier, Grenoble 38000, France; Laboratoire AGIM, CNRS FRE3405, Equipe "Andrologie et Génétique," La Tronche 38700, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Yassine
authors.affiliation: Université Joseph Fourier, Grenoble 38000, France; Laboratoire AGIM, CNRS FRE3405, Equipe "Andrologie et Génétique," La Tronche 38700, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Pierre
authors.affiliation: Université Joseph Fourier, Grenoble 38000, France; INSERM, U836, Grenoble Institute of Neuroscience, La Tronche 38700, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Delaroche
authors.affiliation: Université Joseph Fourier, Grenoble 38000, France; Laboratoire AGIM, CNRS FRE3405, Equipe "Andrologie et Génétique," La Tronche 38700, France; CHU de Grenoble, Hôpital Couple Enfant, Département de Génétique et Procréation, Laboratoire d'Aide à la Procréation - CECOS, Grenoble 38000, France.
authors.forename: Sylviane
authors.initials: S
authors.lastname: Hennebicq
authors.affiliation: Université Joseph Fourier, Grenoble 38000, France; INSERM, U836, Grenoble Institute of Neuroscience, La Tronche 38700, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Grunwald
authors.affiliation: INSERM UMR_S933, Université Pierre et Marie Curie (Paris 6), Paris 75012, France.
authors.forename: Denise
authors.initials: D
authors.lastname: Escalier
authors.affiliation: Université Joseph Fourier, Grenoble 38000, France; INSERM, U836, Grenoble Institute of Neuroscience, La Tronche 38700, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Pernet-Gallay
authors.affiliation: Université Joseph Fourier-Grenoble 1 / CNRS / TIMC-IMAG UMR 5525, Grenoble 38041, France; CHU de Grenoble, Hôpital Couple Enfant, Département de Génétique et Procréation, Service de Génétique Clinique, Grenoble 38000, France.
authors.forename: Pierre-Simon
authors.initials: PS
authors.lastname: Jouk
authors.affiliation: Université Joseph Fourier-Grenoble 1 / CNRS / TIMC-IMAG UMR 5525, Grenoble 38041, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Thierry-Mieg
authors.affiliation: INSERM, U1016, Institut Cochin, Paris 75014, France; CNRS, UMR8104, Paris 75014, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris 75014, France.
authors.forename: Aminata
authors.initials: A
authors.lastname: Touré
authors.affiliation: Université Joseph Fourier, Grenoble 38000, France; Laboratoire AGIM, CNRS FRE3405, Equipe "Andrologie et Génétique," La Tronche 38700, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Arnoult
authors.affiliation: Université Joseph Fourier, Grenoble 38000, France; Laboratoire AGIM, CNRS FRE3405, Equipe "Andrologie et Génétique," La Tronche 38700, France; CHU de Grenoble, Institut de Biologie et Pathologie, Département de Biochimie, Toxicologie et Pharmacologie (DBTP), UF de Biochimie et Génétique Moléculaire, Grenoble 38000, France. Electronic address: pray@chu-grenoble.fr.
authors.forename: Pierre F
authors.initials: PF
authors.lastname: Ray
mesh_terms: D056444:Axonemal Dyneins / Q000235:genetics*; D054468:Axoneme / Q000235:genetics / Q000473:pathology; D002923:Cilia / Q000235:genetics / Q000473:pathology; D005407:Flagella / Q000473:pathology; D014644:Genetic Variation; D006720:Homozygote; D006801:Humans; D007248:Infertility, Male / Q000235:genetics*; D007619:Kartagener Syndrome / Q000235:genetics; D008297:Male; D009154:Mutation; D022821:RNA Splice Sites; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013081:Sperm Motility; D013082:Sperm Tail / Q000473:pathology*; D013737:Testis / Q000166:cytology / Q000473:pathology
chemical_list: D022821:RNA Splice Sites; D012333:RNA, Messenger; D056444:Axonemal Dyneins; C465433:DNAH11 protein, human