Disruption of an inner arm dynein heavy chain gene results in asthenozoospermia and reduced ciliary beat frequency

Abstract

Impaired ciliary and flagellar functions resulting in male infertility and recurrent respiratory tract infections are found in patients suffering from primary ciliary dyskinesia (PCD). In most cases, axonemal defects are present, i.e. PCD patients often lack inner and/or outer dynein arms in their sperm tails and cilia, supporting the hypothesis that mutations in dynein genes may cause PCD. However, to date it is unclear whether mutations in dynein heavy chain genes are responsible for impaired flagellar and ciliary motility in mammals. To elucidate the role of the mouse dynein heavy chain 7 (MDHC7) gene, which encodes a component of the inner dynein arm, we have generated mice lacking this dynein heavy chain isoform. Both MDHC7(+/-) and MDHC7(-/-) mice are viable and show no malformations; however, homozygous males produce no offspring. In comparison to MDHC7(+/-) and wild-type mice the spermatozoa of MDHC7(-/-) mice revealed a dramatic reduced straight line velocity and progressive movement, resulting in the inability of MDHC7-deficient sperm to move from the uterus into the oviduct. Additionally, we measured the beat frequency of tracheal cilia and observed a decrease in the beat frequency of approximately 50% in MDHC7(-/-) mice. The reduction in both ciliary and flagellar motility is not correlated with any gross defects in the axonemal structure. The phenotype of MDHC7(-/-) mice is similar to that observed in some patients suffering from PCD, and our data strongly suggest that in some patients this disease could be due to mutations in the homologous human gene DNAH1 (HDHC7).

ATPases, ion exchangers and human sperm motility

“…They both play a crucial role in tubular sliding for the generation of sperm motility. The absence of the dynein arms, seen in some syndromes, leads to impairment of sperm motility and male infertility (Afzelius et al 1975, Jouannet et al 1983, Goodenough & Heuser 1985, Neesen et al 2001. Moreover, Gibbons (1965Gibbons ( , 1974 demonstrated that dyneins exhibit ATPase activity, and our group has recently developed a straightforward assay to test dynein-ATPase activity (Vívenes et al 2009).…”

Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella

“…9 Previous studies on genetic mutants in model organisms have revealed genetic contributions to flagellar motility defects. 2,[10][11][12][13][14] So far, mutations in only three genes, AKAP4 (MIM: 300185), CCDC39 (MIM: 613798), and DNAH1 (MIM: 603332), have been formally identified to cause MMAF in humans. 2,3,15,16 Among them, biallelic DNAH1 mutations in MMAF have been recurrently identified across studies and account for 28%-44% of MMAF cases.…”

Centimorgan-Range One-Step Mapping of Fertility Traits Using Interspecific Recombinant Congenic Mice

“…Indeed, the molecular basis of male infertility is determined in only $10% of the cases; these patients are essentially azoospermic or severely oligospermic, owing to microdeletions in the AZF region (the major cluster of genes influencing sperm count; for review, see Affara and Mitchell 2000) at Yq11 (Foresta et al 2001). Genes governing sperm shape (Mendoza-Lujambio et al 2002;Nakamura et al 2004), acrosome formation (Yaoet al 2002), or sperm movement (Pilder et al 1997;Neesen et al 2001;Carlson et al 2003) have also been shown to cause infertility in mouse-gene-targeting models.…”