• PMID: 31621862
• Gene Name: CFAP70
• Condition: Multiple morphological abnormalities of the sperm flagella (MMAF)
• Association: Associated
• Mutation: c.1723-1G>T, missense variant in exon 3 (p.Phe60Ile)
• Population size: 167
• Population details: 167 MMAF-affected subjects
• Sex: Male
• Infertility type: Male infertility
• Associated genes: NGS

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

Beurois J, Martinez G, Cazin C, Kherraf ZE, Amiri-Yekta A, Thierry-Mieg N, Bidart M, Petre G, Satre V, Brouillet S, Touré A, Arnoult C, Ray PF, Coutton C.

The use of high-throughput sequencing techniques has allowed the identification of numerous mutations in genes responsible for severe astheno-teratozoospermia due to multiple morphological abnormalities of the sperm flagella (MMAF). However, more than half of the analysed cases remain unresolved suggesting that many yet uncharacterised gene defects account for this phenotype. Based on whole-exome sequencing data from a large cohort of 167 MMAF-affected subjects, we identified two unrelated affected individuals carrying a homozygous deleterious mutation in CFAP70, a gene not previously linked to the MMAF phenotype. One patient had a homozygous splice variant c.1723-1G>T, altering a consensus splice acceptor site of CFAP70 exon 16, and one had a likely deleterious missense variant in exon 3 (p.Phe60Ile). The CFAP70 gene encodes a regulator protein of the outer dynein arms (ODA) strongly expressed in the human testis. In the sperm cells from the patient carrying the splice variant, immunofluorescence (IF) experiments confirmed the absence of the protein in the sperm flagellum. Moreover, IF analysis showed the absence of markers for the ODAs and the central pair complex of the axoneme. Interestingly, whereas CFAP70 staining was present in sperm cells from patients with mutations in the three other MMAF-related genes ARMC2, FSIP2 and CFAP43, we observed an absence of staining in sperm cells from patients mutated in the WDR66 gene, suggesting a possible interaction between two different axonemal components. In conclusion, this work provides the first evidence that loss of CFAP70 function causes MMAF and that ODA-related proteins may be crucial for the assembly and/or stability of the flagellum axoneme in addition to its motility. CI - © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. FAU - Beurois, Julie AU - Beurois J AD - INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Université Grenoble Alpes, 38000 Grenoble, France. FAU - Martinez, Guillaume AU - Martinez G AD - INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Université Grenoble Alpes, 38000 Grenoble, France. AD - CHU Grenoble Alpes, UM de Génétique Chromosomique, Grenoble, France. FAU - Cazin, Caroline AU - Cazin C AD - INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Université Grenoble Alpes, 38000 Grenoble, France. FAU - Kherraf, Zine-Eddine AU - Kherraf ZE AD - INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Université Grenoble Alpes, 38000 Grenoble, France. AD - CHU de Grenoble, UM GI-DPI, Grenoble, F-38000, France. FAU - Amiri-Yekta, Amir AU - Amiri-Yekta A AD - Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran. FAU - Thierry-Mieg, Nicolas AU - Thierry-Mieg N AD - CNRS, TIMC-IMAG, Université Grenoble Alpes, F-38000 Grenoble, France. FAU - Bidart, Marie AU - Bidart M AD - INSERM U1205, UFR Chimie Biologie, Université Grenoble Alpes, Grenoble, France. FAU - Petre, Graciane AU - Petre G AD - INSERM U1205, UFR Chimie Biologie, Université Grenoble Alpes, Grenoble, France. FAU - Satre, Véronique AU - Satre V AD - INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Université Grenoble Alpes, 38000 Grenoble, France. AD - CHU Grenoble Alpes, UM de Génétique Chromosomique, Grenoble, France. FAU - Brouillet, Sophie AU - Brouillet S AD - Laboratoire d'AMP-CECOS, CHU Grenoble-Alpes, U1036 INSERM-UGA-CEA-CNRS, Université Grenoble Alpes, 38000 Grenoble, France. FAU - Touré, Aminata AU - Touré A AD - INSERM U1016, Institut Cochin, Paris 75014, France. AD - UMR 8104, Centre National de la Recherche Scientifique, Paris 75014, France. AD - Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France. FAU - Arnoult, Christophe AU - Arnoult C AD - INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Université Grenoble Alpes, 38000 Grenoble, France. FAU - Ray, Pierre F AU - Ray PF AD - INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Université Grenoble Alpes, 38000 Grenoble, France. AD - CHU de Grenoble, UM GI-DPI, Grenoble, F-38000, France.