A missense mutation in IFT74, encoding for an essential component for intraflagellar transport of Tubulin, causes asthenozoospermia and male infertility without clinical signs of Bardet-Biedl syndrome.

Autor: Lorès P; Université de Paris, Institut Cochin, INSERM, CNRS, 75014, Paris, France., Kherraf ZE; Université Grenoble Alpes, Institut pour l'avancée des Biosciences, INSERM, CNRS, 38000, Grenoble, France.; CHU de Grenoble, UM GI-DPI, 38000, Grenoble, France., Amiri-Yekta A; Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran., Whitfield M; Université Grenoble Alpes, Institut pour l'avancée des Biosciences, INSERM, CNRS, 38000, Grenoble, France., Daneshipour A; Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran., Stouvenel L; Université de Paris, Institut Cochin, INSERM, CNRS, 75014, Paris, France., Cazin C; Université Grenoble Alpes, Institut pour l'avancée des Biosciences, INSERM, CNRS, 38000, Grenoble, France.; CHU de Grenoble, UM GI-DPI, 38000, Grenoble, France., Cavarocchi E; Université Grenoble Alpes, Institut pour l'avancée des Biosciences, INSERM, CNRS, 38000, Grenoble, France., Coutton C; Université Grenoble Alpes, Institut pour l'avancée des Biosciences, INSERM, CNRS, 38000, Grenoble, France.; CHU Grenoble Alpes, UM de Génétique Chromosomique, Grenoble, France., Llabador MA; Laboratoire de Biologie de la Reproduction, Groupe Hospitalier Universitaire Paris Nord Val de Seine, Assistante Publique-Hôpitaux de Paris, 75018, Paris, France., Arnoult C; Université Grenoble Alpes, Institut pour l'avancée des Biosciences, INSERM, CNRS, 38000, Grenoble, France., Thierry-Mieg N; Univ. Grenoble Alpes, CNRS, TIMC-IMAG/BCM, 38000, Grenoble, France., Ferreux L; Université de Paris, Institut Cochin, INSERM, CNRS, 75014, Paris, France.; Laboratoire d'Histologie Embryologie, Biologie de la Reproduction, CECOS Groupe Hospitalier Universitaire Paris Centre, Assistance Publique-Hôpitaux de Paris, 75014, Paris, France., Patrat C; Université de Paris, Institut Cochin, INSERM, CNRS, 75014, Paris, France.; Laboratoire d'Histologie Embryologie, Biologie de la Reproduction, CECOS Groupe Hospitalier Universitaire Paris Centre, Assistance Publique-Hôpitaux de Paris, 75014, Paris, France., Hosseini SH; Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran., Mustapha SFB; Polyclinique les Jasmins, Centre d'Aide Médicale à la Procréation, Centre Urbain Nord, 1003, Tunis, Tunisia., Zouari R; Polyclinique les Jasmins, Centre d'Aide Médicale à la Procréation, Centre Urbain Nord, 1003, Tunis, Tunisia., Dulioust E; Université de Paris, Institut Cochin, INSERM, CNRS, 75014, Paris, France.; Laboratoire d'Histologie Embryologie, Biologie de la Reproduction, CECOS Groupe Hospitalier Universitaire Paris Centre, Assistance Publique-Hôpitaux de Paris, 75014, Paris, France., Ray PF; Université Grenoble Alpes, Institut pour l'avancée des Biosciences, INSERM, CNRS, 38000, Grenoble, France.; CHU de Grenoble, UM GI-DPI, 38000, Grenoble, France., Touré A; Université Grenoble Alpes, Institut pour l'avancée des Biosciences, INSERM, CNRS, 38000, Grenoble, France. aminata.toure@inserm.fr.
Jazyk: angličtina
Zdroj: Human genetics [Hum Genet] 2021 Jul; Vol. 140 (7), pp. 1031-1043. Date of Electronic Publication: 2021 Mar 10.
DOI: 10.1007/s00439-021-02270-7
Abstrakt: Cilia and flagella are formed around an evolutionary conserved microtubule-based axoneme and are required for fluid and mucus clearance, tissue homeostasis, cell differentiation and movement. The formation and maintenance of cilia and flagella require bidirectional transit of proteins along the axonemal microtubules, a process called intraflagellar transport (IFT). In humans, IFT defects contribute to a large group of systemic diseases, called ciliopathies, which often display overlapping phenotypes. By performing exome sequencing of a cohort of 167 non-syndromic infertile men displaying multiple morphological abnormalities of the sperm flagellum (MMAF) we identified two unrelated patients carrying a homozygous missense variant adjacent to a splice donor consensus site of IFT74 (c.256G > A;p.Gly86Ser). IFT74 encodes for a core component of the IFT machinery that is essential for the anterograde transport of tubulin. We demonstrate that this missense variant affects IFT74 mRNA splicing and induces the production of at least two distinct mutant proteins with abnormal subcellular localization along the sperm flagellum. Importantly, while IFT74 deficiency was previously implicated in two cases of Bardet-Biedl syndrome, a pleiotropic ciliopathy with variable expressivity, our data indicate that this missense mutation only results in primary male infertility due to MMAF, with no other clinical features. Taken together, our data indicate that the nature of the mutation adds a level of complexity to the clinical manifestations of ciliary dysfunction, thus contributing to the expanding phenotypical spectrum of ciliopathies.
Databáze: MEDLINE
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