Team
Genetics, Epigenetics and therapies of infertility

Dpt: Environnement, Reproduction, Infections, Cancer

Our research activities

Infertility is a common condition and 1 in 7 couples will need medical assistance to procreate. For couples with the most severe phenotypes, their management will require the use of medically assisted reproduction techniques, which are complex and have a significant financial cost. Among these couples, 1 out of 2 will come out of this difficult process without a child, with important consequences in terms of well-being for the couples involved. Two major reasons explain these failures: 1/ our poor understanding of the molecular pathogenesis of many infertilities and 2/ these techniques are only palliative and do not restore the deficient functions of the gametes or the reproductive system of the patients. To address these major problems of infertility, we have developed a research program aimed at:

  • characterize the genes involved in male and female infertility
  • to understand the cellular role of the identified proteins and thus to discover new actors of gametogenesis.  This also allows us to characterize the molecular pathogenesis of infertility.
  • propose improvements to assisted reproductive technologies or alternative therapies in the field of male infertility, taking into account our discoveries on the causes of infertility.

Christophe ARNOULT

Team leader

Pierre RAY

Team leader

Our research axes

This work is based on a multicenter cohort of patients (Grenoble Alpes University Hospital) whose exome sequencing has been carried out progressively over the last 10 years (~1,200 exomes currently available). In recent years, we have focused on several infertility phenotypes, such as: 1)multiple morphological abnormalities of the flagellum (MMAF), 2) non-obstructive azoospermia (NOA), 3) fertilization failures, and 4) oocyte maturation arrest. 

The objective of this part of the research program is to characterize the localization, identify molecular partners, and establish the function of the proteins under investigation. This work relies on the creation of specific tools (antibodies, KI/KO mice, transgenic mice with labeled (fluorescent) proteins) and aims to improve our understanding of gametogenesis by characterizing new molecular players and new signaling pathways, as well as improving our knowledge of molecular pathogenesis.

Despite remarkable advances in infertility treatment over the past few decades, 1 in 2 couples still fail to conceive. Our goal is to develop new treatment strategies for these couples or improve current techniques. Identifying the genetic causes of male infertility allows us to evaluate a new approach to infertility treatment based on restoring the protein deficient in gametogenesis and to develop protocols for personalized medicine using mRNA and lipid nanoparticle (LNP) technologies.

Our major publications

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Oligogenic heterozygous inheritance of sperm abnormalities in mouse

Martinez G, Coutton C, Loeuillet C, Cazin C, Muroňová J, Boguenet M, Lambert E, Dhellemmes…

Elife 2022 Apr 22;11:e75373. doi: 10.7554/eLife.75373.

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Whole-exome sequencing improves the diagnosis and care of men with non-obstructive azoospermia

Kherraf ZE, Cazin C, Bouker A, Fourati Ben Mustapha S, Hennebicq S, Septier A, Coutton…

Am J Hum Genet 2022 Mar 3;109(3):508-517. doi: 10.1016/j.ajhg.2022.01.011. Epub 2022 Feb 15

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Biallelic mutations in ARMC2 lead to severe astheno-teratozoospermia due to sperm flagellum malformations (MMAF) in human and mouse

Coutton C., Martinez G., …Thierry-Mieg N., Arnoult C. * and Ray P.F.

American Journal of Human genetics 2019 104(2):331-340 IF 8.85 *co dernier auteur

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CFAP70 mutations lead to male infertility due to severe astheno-teratozoospermia. A case report.

Beurois J, Martinez G, …, Arnoult C, Ray PF, Coutton C.

Hum Reprod 2019 34(10): 2071-2079. IF 5.72

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A homozygous ancestral SVA-insertion mediated deletion in WDR66 induces multiple morphological abnormalities of the sperm flagellum and male infertility

Kherraf Z.E., Amiri-Yekta A., …, Arnoult C., Bonhivers M. and Ray P.F.

American Journal of Human genetics 2018 103(3):400-412. doi: 10.1016/j.ajhg.2018.07.014 IF 10.36

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Absence of cilia- and flagella-associated protein 69 (CFAP69) causes male infertility due to multiple morphological abnormalities of the flagella (MMAF) in human and mouse

Dong F.N., Amiri-Yekta A., …. Arnoult C., Touré A. , Ray P.F., Zhao H., Coutton…

American Journal of Human genetics 2018 102: 636-648. doi: 10.1016/j.ajhg.2018.03.007 IF IF 8.85

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Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human

Coutton C, Vargas AS, …., Arnoult C, Ray PF.

Nature Comm 2018 9: 686-96. doi: 10.1038/s41467-017-02792-7* co dernier auteur IF 12.12

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PATL2 is a key actor of oocyte maturation whose invalidation causes infertility in women and mice

Christou-Kent M. , Zine-Eddine Kherraf Z-E, …. and Arnoult C.

EMBO Molecular Medicine 2018 10(5). pii: e8515. doi: 10.15252/emmm.201708515 IF 9.50

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Whole-exome sequencing identifies mutations in the Fibrous Sheath Interaction Protein 2 (FSIP2) as a recurrent cause of multiple morphological abnormalities of the sperm flagella (MMAF)

Martinez G., Raoudha Zouari R., …., Arnoult C., Ray P.F., Coutton C.

Human reproduction 2018 33(10):1973-1984. doi: 10.1093/humrep/dey264 IF 5.00

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SPINK2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes

Kherraf Z., Christou-Kent M., ….. and Arnoult C.

EMBO Molecular Medicine 2017 9:1132-1149. doi: 10.15252/emmm.201607461 IF 9.24

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Our activities in pictures

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Our collaborations

  • Sege Nef Unige, Genève, Switzerland - Generation of models to study gametogenesis
  • Rafael Fissore Umass, Mass, USA - Study of oocyte activation
  • Rahouda Zouari Clinique des Jasmins, Tunisia - Patient’s recruitment
  • Amir Aminiri Royan institute, Iran - Patient’s recruitment and molecular biology
  • Feng Zhang Fudan University, Shanghai, China - Genetics of MMAF patients Generation of animal models
  • Nicolas Tierry-Mieg CNRS, TIMC, University of Grenoble - Analyses of genome wide data
  • Gérard Lambeau CNRS, IPMC, University of Sophia - Antipolis. Role of sPLA2 in embryonic development
  • Mélanie Bonhivers CNRS, Bordeaux - Trypanosoma models for MMAF
  • Michael Mitchell Aix-Marseille University - Genetics of azoospermia
  • Chiara Piavolo, Univ. Grenoble Alpes, CEA, LETI, DTBS, 38000, Grenoble, France - Development of holographic microscopy
  • Aminata Touré IAB - Characterization of genes involved in flagellum defects
  • Saadi Khochbin IAB - Epigenetic of sperm
  • Stefan Dimitrov IAB - Importance of H3.3 in spermatogenesis
  • Frank Tüttelmann, Centre of Medical Genetics - Münster, Germany.
  • Claire Monge, Laboratory of Tissue Biology and Therapeutic Engineering, Lyon, France. LNP Production.
  • Philippe Robert, Guerbet-France

Our technologies

  • Technique de procréation médicalement assistée (CASA, IVF, ICSI et IUU)
  • Biologie moléculaire et séquençage
  • Biochimie
  • Microscopie