DNAH11 explained

DNAH11 and common names

Dynein axonemal heavy chain 11 (DNAH11) is a protein that is encoded by the DNAH11 gene in humans.[1] [2] In mice, the protein is encoded by the Dnahc11 gene, the murine homolog to human DNAH11.[3] 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.[4] [5]

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 gene DNAH11 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.[6] [7] [8] 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.[9] [10] These cilia are responsible for directing increased amounts of nodal to the left side of the developing embryo, establishing asymmetry. 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. 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.[11] [12] 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).

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.[13] [14] For this reason, males with PCD are not sterile, but they are often infertile under conventional methods due to lack of sperm motility; however, there are cases of DNAH11 mutant males fathering offspring without intervention of assisted reproductive technologies.[15] [16] In females with PCD or Kartagener's syndrome, there are increased reports of subfertility and risk of ectopic pregnancy.[17] [18] 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).[19]

Further reading

External links

Notes and References

  1. Chapelin C, Duriez B, Magnino F, Goossens M, Escudier E, Amselem S . 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 . Sep 1997 . 9256245 . 10.1016/S0014-5793(97)00800-4 . 23935907 .
  2. Web site: Entrez Gene: DNAH11 dynein, axonemal, heavy chain 11.
  3. Lucas, 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
  4. 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
  5. Xia, H., Huang, X., Deng, S., Xu, H., Yang, Y., Liu, X., ... & Deng, H. (2021). DNAH11 compound heterozygous variants cause heterotaxy and congenital heart disease. PLoS One, 16(6), e0252786. https://doi.org/10.1371/journal.pone.0252786
  6. Zhu . Dongliang . Zhang . Hongguo . Wang . Ruixue . Liu . Xiaojun . Jiang . Yuting . Feng . Tao . Liu . Ruizhi . Zhang . Guirong . June 2019 . Association of DNAH11 gene polymorphisms with asthenozoospermia in Northeast Chinese patients . Bioscience Reports . 39 . 6 . 10.1042/bsr20181450 . 0144-8463 . 6617048 . 31160482.
  7. Zariwala . Maimoona A. . Knowles . Michael R. . Omran . Heymut . 2007-03-01 . Genetic Defects in Ciliary Structure and Function . Annual Review of Physiology . en . 69 . 1 . 423–450 . 10.1146/annurev.physiol.69.040705.141301 . 17059358 . 0066-4278.
  8. Wagner . M. K. . Yost . H. J. . 2000-02-15 . Left–right development: The roles of nodal cilia . Current Biology . English . 10 . 4 . R149–R151 . 10.1016/S0960-9822(00)00328-6 . 0960-9822 . 10704402. free . 2000CBio...10.R149W .
  9. Harvey . Richard P. . 1998-08-07 . Links in the Left/Right Axial Pathway . Cell . English . 94 . 3 . 273–276 . 10.1016/S0092-8674(00)81468-3 . 0092-8674 . 9708727. free .
  10. Grabowski . Casimer T. . August 1962 . Neural induction and notochord formation by mesoderm from the node area of the early chick blastoderm . Journal of Experimental Zoology . en . 150 . 3 . 233–245 . 10.1002/jez.1401500307 . 13949682 . 1962JEZ...150..233G . 0022-104X.
  11. Bartoloni . Lucia . Blouin . Jean-Louis . Pan . Yanzhen . Gehrig . Corinne . Maiti . Amit K. . Scamuffa . Nathalie . Rossier . Colette . Jorissen . Mark . Armengot . Miguel . Meeks . Maggie . Mitchison . Hannah M. . Chung . Eddie M. K. . Delozier-Blanchet . Celia D. . Craigen . William J. . Antonarakis . Stylianos E. . 2002-08-06 . Mutations in the DNAH11 (axonemal heavy chain dynein type 11) gene cause one form of situs inversus totalis and most likely primary ciliary dyskinesia . Proceedings of the National Academy of Sciences . en . 99 . 16 . 10282–10286 . 10.1073/pnas.152337699 . free . 0027-8424 . 124905 . 12142464. 2002PNAS...9910282B .
  12. Russakoff . A. H. . Katz . Harvey W. . 1946-08-22 . Dextrocardia and Bronchiectasis: A Review of the Literature and a Report of Two Cases . New England Journal of Medicine . en . 235 . 8 . 253–255 . 10.1056/NEJM194608222350803 . 20996259 . 0028-4793.
  13. Whitfield . Marjorie . Thomas . Lucie . Bequignon . Emilie . Schmitt . Alain . Stouvenel . Laurence . Montantin . Guy . Tissier . Sylvie . Duquesnoy . Philippe . Copin . Bruno . Chantot . Sandra . Dastot . Florence . Faucon . Catherine . Barbotin . Anne Laure . Loyens . Anne . Siffroi . Jean-Pierre . 2019-07-03 . Mutations in DNAH17, Encoding a Sperm-Specific Axonemal Outer Dynein Arm Heavy Chain, Cause Isolated Male Infertility Due to Asthenozoospermia . The American Journal of Human Genetics . English . 105 . 1 . 198–212 . 10.1016/j.ajhg.2019.04.015 . 0002-9297 . 6612517 . 31178125.
  14. Sironen . Anu . Shoemark . Amelia . Patel . Mitali . Loebinger . Michael R. . Mitchison . Hannah M. . 2019-11-28 . Sperm defects in primary ciliary dyskinesia and related causes of male infertility . Cellular and Molecular Life Sciences . 77 . 11 . 2029–2048 . 10.1007/s00018-019-03389-7 . 31781811 . 1420-682X. 7256033 .
  15. Vanaken . Gert Jan . Bassinet . Laurence . Boon . Mieke . Mani . Rahma . Honoré . Isabelle . Papon . Jean-Francois . Cuppens . Harry . Jaspers . Martine . Lorent . Natalie . Coste . André . Escudier . Estelle . Amselem . Serge . Maitre . Bernard . Legendre . Marie . Christin-Maitre . Sophie . 2017-11-01 . Infertility in an adult cohort with primary ciliary dyskinesia: phenotype–gene association . European Respiratory Journal . en . 50 . 5 . 10.1183/13993003.00314-2017 . 0903-1936 . 29122913. free .
  16. Schwabe . Georg C. . Hoffmann . Katrin . Loges . Niki Tomas . Birker . Daniel . Rossier . Colette . de Santi . Margherita M. . Olbrich . Heike . Fliegauf . Manfred . Failly . Mike . Liebers . Uta . Collura . Mirella . Gaedicke . Gerhard . Mundlos . Stefan . Wahn . Ulrich . Blouin . Jean-Louis . February 2008 . Primary ciliary dyskinesia associated with normal axoneme ultrastructure is caused byDNAH11mutations . Human Mutation . 29 . 2 . 289–298 . 10.1002/humu.20656 . 18022865 . 22292489 . 1059-7794.
  17. Blyth M, Wellesley D . April 2008 . Ectopic pregnancy in primary ciliary dyskinesia . J Obstet Gynaecol . 28 . 3 . 358 . 10.1080/01443610802058742 . 18569496 . 19624982.
  18. Halbert . S. A. . Patton . D. L. . Zarutskie . P. W. . Soules . M. R. . 1997-01-01 . Function and structure of cilia in the fallopian tube of an infertile woman with Kartagener's syndrome . Human Reproduction . 12 . 1 . 55–58 . 10.1093/humrep/12.1.55 . 0268-1161. free . 9043902 .
  19. Raidt . Johanna . Werner . Claudius . Menchen . Tabea . Dougherty . Gerard W. . Olbrich . Heike . Loges . Niki T. . Schmitz . Ralf . Pennekamp . Petra . Omran . Heymut . 2015-09-15 . Ciliary function and motor protein composition of human fallopian tubes . Human Reproduction . 30 . 12 . 2871–2880 . 10.1093/humrep/dev227 . 1460-2350. free . 26373788 .

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