Dynein axonemal heavy chain 11 (DNAH11) is a
protein that is encoded by the DNAH11gene in humans.[5][6] In mice, the protein is encoded by the Dnahc11 gene, the murine homolog to human DNAH11.[7] The protein was previously known as 'left-right' dynein (with the corresponding gene alias lrd) in mice and is particularly notable during
embryogenesis for orientation of the eventual
body plan.[8][9]
Function
This gene encodes a member of the
dynein heavy chain family, DNAH11, a
microtubule-dependent motor
ATPase protein critical for processes involving
ciliary movement. The
geneDNAH11 has reported associations in a number of important
physiological processes including the movement of respiratory cilia,
sperm motility, and establishment of the adult
body plan.[7][10][11][12] A knockout model of this gene has not been reported.
Embryogenesis
The body plan is naturally
asymmetrical, and the overall order is defined during embryonic
gastrulation in mammals where the three
germ layers (
endoderm,
mesoderm, and
ectoderm) are established. At the beginnings of gastrulation, the
primitive node serves as the
organizer and has motile cilia on its surface.[13][14] These cilia are responsible for directing increased amounts of
nodal to the left side of the developing embryo, establishing asymmetry.[7] For this reason, proper expression of DNAH11 is critical for correct establishment and subsequent development of the asymmetrical body plan.
Conditions Associated with DNAH11
Mutations in this DNAH11 have been implicated in causing
Primary Ciliary Dyskinesia (PCD), formerly called
'immotile cilia syndrome', and results from abnormally motile or static cilia within the respiratory tract.[7] PCD is characterized by bronchiectasis, frequent upper respiratory tract infections, and issues with fertility, and PCD individuals have increased rates of
heterotaxy and situs inversus in approximately 50% of reported cases, a
congenital condition in which some organs are mirrored to an abnormal side of the body cavity.[15][16] Mutations in DNAH11 are also associated with
Kartagener syndrome (PCD with situs inversus totalis, a congenital condition with a characteristic total inversion of the body plan and organs).[15]
Fertility-Related Effects
Genetic errors with DNAH11 have been shown to cause a number of fertility-related effects in both sexes. Decreased motile cilia-specific expression of DNAH11 within the
axoneme of sperm is associated with lower levels of sperm motility.[17][18] For this reason, males with PCD are not sterile, but they are often
infertile under conventional methods due to lack of sperm
motility;[6][18] however, there are cases of DNAH11 mutant males fathering offspring without intervention of
assisted reproductive technologies.[19][20] In females with PCD or Kartagener's syndrome, there are increased reports of subfertility and risk of
ectopic pregnancy.[21][22] Because females'
fallopian tubes are lined with motile cilia which show identical motor protein composition to those observed in the
respiratory tract, this is believed to result in the increased risks observed in case studies (although affected PCD females' cilia have not been directly analyzed so this remains inconclusive).[23]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Chapelin C, Duriez B, Magnino F, Goossens M, Escudier E, Amselem S (Sep 1997). "Isolation of several human axonemal dynein heavy chain genes: genomic structure of the catalytic site, phylogenetic analysis and chromosomal assignment". FEBS Lett. 412 (2): 325–30.
doi:
10.1016/S0014-5793(97)00800-4.
PMID9256245.
S2CID23935907.
^
abcdLucas, J. S., Adam, E. C., Goggin, P. M., Jackson, C. L., Powles‐Glover, N., Patel, S. H., ... & Lackie, P. M. (2012). Static respiratory cilia associated with mutations in Dnahc11/DNAH11: a mouse model of PCD. Human mutation, 33(3), 495-503.
https://doi.org/10.1002/humu.22001
^Supp, D. M., Brueckner, M., Kuehn, M. R., Witte, D. P., Lowe, L. A., McGrath, J., ... & Potter, S. S. (1999). Targeted deletion of the ATP binding domain of left-right dynein confirms its role in specifying development of left-right asymmetries. Development, 126(23), 5495-5504.
https://doi.org/10.1242/dev.126.23.5495
Kastury K, Taylor WE, Gutierrez M, et al. (1997). "Chromosomal mapping of two members of the human dynein gene family to chromosome regions 7p15 and 11q13 near the deafness loci DFNA 5 and DFNA 11". Genomics. 44 (3): 362–4.
doi:
10.1006/geno.1997.4903.
PMID9325061.