Mutations in DNAH1, which Encodes an Inner Arm Heavy Chain Dynein, Lead to Male Infertility from Multiple Morphological Abnormalities of the Sperm Flagella

• Published in: American journal of human genetics Vol. 94; no. 1; pp. 95 - 104
• Main Authors: Ben Khelifa, Mariem, Coutton, Charles, Zouari, Raoudha, Karaouzène, Thomas, Rendu, John, Bidart, Marie, Yassine, Sandra, Pierre, Virginie, Delaroche, Julie, Hennebicq, Sylviane, Grunwald, Didier, Escalier, Denise, Pernet-Gallay, Karine, Jouk, Pierre-Simon, Thierry-Mieg, Nicolas, Touré, Aminata, Arnoult, Christophe, Ray, Pierre F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.01.2014; Cell Press; Elsevier (Cell Press); Elsevier
• Subjects: Axonemal Dyneins; Axonemal Dyneins - genetics; Axoneme; Axoneme - genetics; Axoneme - pathology; Cilia; Cilia - genetics; Cilia - pathology; Flagella; Flagella - pathology; Genetic Variation; Genetics; Homozygote; Humans; Infertility; Infertility, Male; Infertility, Male - genetics; Kartagener Syndrome; Kartagener Syndrome - genetics; Life Sciences; Male; Males; Microscopy; Morphology; Mutation; Proteins; RNA Splice Sites; RNA, Messenger; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sequence Analysis, DNA; Sperm; Sperm Motility; Sperm Tail; Sperm Tail - pathology; Testis; Testis - cytology; Testis - pathology
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2013.11.017

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.