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Am J Hum Genet. 2018 Apr 5;102(4):636-648. doi: 10.1016/j.ajhg.2018.03.007.

Absence of CFAP69 Causes Male Infertility due to Multiple Morphological Abnormalities of the Flagella in Human and Mouse.

Author information

1
Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
2
Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran; Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, 38000 Grenoble, France.
3
Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, 38000 Grenoble, France; CHU Grenoble Alpes, UM de Génétique Chromosomique, 38000 Grenoble, France.
4
INSERM U1016, Institut Cochin, Paris 75014, France; Centre National de la Recherche Scientifique UMR8104, Paris 75014, France; Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France.
5
Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, 38000 Grenoble, France; CHU de Grenoble, UM GI-DPI, Grenoble 38000, France; Université Grenoble Alpes / CNRS, TIMC-IMAG, 38000 Grenoble, France.
6
Université Grenoble Alpes / CNRS, TIMC-IMAG, 38000 Grenoble, France.
7
Université Grenoble-Alpes, Laboratoire d'AMP-CECOS CHU de Grenoble-Alpes, U1036 INSERM-UGA-CEA-CNRS, 38000 Grenoble, France.
8
Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.
9
Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran-Iran.
10
Université de Bordeaux, Microbiologie Fondamentale et Pathogénicité, CNRS UMR 5234, 33000 Bordeaux, France; Institut Polytechnique de Bordeaux, Microbiologie Fondamentale et Pathogénicité, UMR-CNRS 5234, 33000 Bordeaux, France.
11
Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France; Laboratoire d'Histologie Embryologie - Biologie de la Reproduction, GH Cochin Broca Hôtel Dieu, Assistance Publique-Hôpitaux de Paris, Paris 75014, France.
12
Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, 38000 Grenoble, France.
13
Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, 38000 Grenoble, France; CHU de Grenoble, UM GI-DPI, Grenoble 38000, France.
14
Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA. Electronic address: hzhao@jhu.edu.
15
Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, 38000 Grenoble, France; CHU Grenoble Alpes, UM de Génétique Chromosomique, 38000 Grenoble, France. Electronic address: ccoutton@chu-grenoble.fr.

Abstract

The multiple morphological abnormalities of the flagella (MMAF) phenotype is among the most severe forms of sperm defects responsible for male infertility. The phenotype is characterized by the presence in the ejaculate of immotile spermatozoa with severe flagellar abnormalities including flagella being short, coiled, absent, and of irregular caliber. Recent studies have demonstrated that MMAF is genetically heterogeneous, and genes thus far associated with MMAF account for only one-third of cases. Here we report the identification of homozygous truncating mutations (one stop-gain and one splicing variant) in CFAP69 of two unrelated individuals by whole-exome sequencing of a cohort of 78 infertile men with MMAF. CFAP69 encodes an evolutionarily conserved protein found at high levels in the testis. Immunostaining experiments in sperm from fertile control individuals showed that CFAP69 localized to the midpiece of the flagellum, and the absence of CFAP69 was confirmed in both individuals carrying CFPA69 mutations. Additionally, we found that sperm from a Cfap69 knockout mouse model recapitulated the MMAF phenotype. Ultrastructural analysis of testicular sperm from the knockout mice showed severe disruption of flagellum structure, but histological analysis of testes from these mice revealed the presence of all stages of the seminiferous epithelium, indicating that the overall progression of spermatogenesis is preserved and that the sperm defects likely arise during spermiogenesis. Together, our data indicate that CFAP69 is necessary for flagellum assembly/stability and that in both humans and mice, biallelic truncating mutations in CFAP69 cause autosomal-recessive MMAF and primary male infertility.

KEYWORDS:

CFAP69; KO mouse model; MMAF; asthenozoospermia; infertility genetics; male infertility; manchette; sperm flagellum; teratozoospermia; whole-exome sequencing

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