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

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 pres ent, i.e, PCD patients often lack inner and/or outer dynein arms in their s perm tails and cilia, supporting the hypothesis that mutations in dynein ge nes may cause PCD, However, to date it is unclear whether mutations in dyne in heavy chain genes are responsible for impaired flagellar and ciliary mot ility 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 gen erated mice lacking this dynein heavy chain isoform, Both MDHC7(+/-) and MD HC7(-/-) mice are viable and show no malformations; however, homozygous mal es produce no offspring. In comparison to MDHC7(+/-) and wild-type mice the spermatozoa of MDHC7(-/-) mice revealed a dramatic reduced straight line v elocity and progressive movement, resulting in the inability of MDHC7-defic ient sperm to move from the uterus into the oviduct, Additionally, we measu red the beat frequency of tracheal cilia and observed a decrease in the bea t frequency of similar to 50% in MDHC7(-/-) mice. The reduction in both cil iary and flagellar motility is not correlated with any gross defects in the axonemal structure, The phenotype of MDHC7(-/-) mice is similar to that ob served in some patients suffering from PCD, and our data strongly suggest t hat in some patients this disease could be due to mutations in the homologo us human gene DNAH1 (HDHC7),