Abstract
Purpose
Primary ciliary dyskinesia (PCD), which commonly causes male infertility, is an inherited autosomal recessive disorder. This study aimed to investigate the clinical manifestations and screen mutations associated with the dynein axonemal assembly factor 2 (DNAAF2) gene in a Han Chinese family with PCD.
Methods
A three-generation family with PCD was recruited in this study. Eight family members underwent comprehensive medical examinations. Genomic DNA was extracted from the participants’ peripheral blood, and targeted next-generation sequencing technology was used to perform the mutation screening. The DNAAF2 expression was analyzed by immunostaining and Western blot.
Results
The proband exhibited the typical clinical features of PCD. Spermatozoa from the proband showed complete immotility but relatively high viability. Two novel compound heterozygous mutations in the DNAAF2 gene, c.C156A [p.Y52X] and c.C26A [p.S9X], were identified. Both nonsense mutations were detected in the proband, whereas the other unaffected family members carried either none or only one of the two mutations. The two nonsense heterozygous mutations were not detected in the 600 ethnically matched normal controls or in the Genome Aggregation Database. The defect of the DNAAF2 and the outer dynein arms and inner dynein arms were notably observed in the spermatozoa from the proband by immunostaining.
Conclusion
This study identified two novel compound heterozygous mutations of DNAAF2 leading to male infertility as a result of PCD in a Han Chinese family. The findings may enhance the understanding of the pathogenesis of PCD and improve reproductive genetic counseling in China.
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References
Mirra V, Werner C, Santamaria F. Primary ciliary dyskinesia: an update on clinical aspects, genetics, diagnosis, and future treatment strategies. Front Pediatr. 2017;5:135.
Lee L. Mechanisms of mammalian ciliary motility: insights from primary ciliary dyskinesia genetics. Gene. 2011;473(2):57–66. https://doi.org/10.1016/j.gene.2010.11.006.
Sha YW, Ding L, Li P. Management of primary ciliary dyskinesia/Kartagener's syndrome in infertile male patients and current progress in defining the underlying genetic mechanism. Asian J Androl. 2014;16(1):101–6.
Bisgrove BW, Yost HJ. The roles of cilia in developmental disorders and disease. Development. 2006;133(21):4131–43. https://doi.org/10.1242/dev.02595.
El Zein L, Omran H, Bouvagnet P. Lateralization defects and ciliary dyskinesia: lessons from algae. Trends Genet. 2003;19(3):162–7. https://doi.org/10.1016/s0168-9525(03)00026-x.
Mitchison HM, Schmidts M, Loges NT, Freshour J, Dritsoula A, Hirst RA, et al. Mutations in axonemal dynein assembly factor DNAAF3 cause primary ciliary dyskinesia. Nat Genet. 2012;44(4):381–9. https://doi.org/10.1038/ng.1106 s1-2.
Afzelius BA. Cilia-related diseases. J Pathol. 2004;204(4):470–7. https://doi.org/10.1002/path.1652.
Omran H, Kobayashi D, Olbrich H, Tsukahara T, Loges NT, Hagiwara H, et al. Ktu/PF13 is required for cytoplasmic pre-assembly of axonemal dyneins. Nature. 2008;456(7222):611–6. https://doi.org/10.1038/nature07471.
Ibanez-Tallon I, Heintz N, Omran H. To beat or not to beat: roles of cilia in development and disease. Hum Mol Genet. 2003;12 Spec(No 1):R27-35.
Bartoloni L, Blouin JL, Pan Y, Gehrig C, Maiti AK, Scamuffa N, et al. Mutations in the DNAH11 (axonemal heavy chain dynein type 11) gene cause one form of situs inversus totalis and most likely primary ciliary dyskinesia. Proc Natl Acad Sci U S A. 2002;99(16):10282–6. https://doi.org/10.1073/pnas.152337699.
Pennarun G, Escudier E, Chapelin C, Bridoux AM, Cacheux V, Roger G, et al. Loss-of-function mutations in a human gene related to Chlamydomonas reinhardtii dynein IC78 result in primary ciliary dyskinesia. Am J Hum Genet. 1999;65(6):1508–19. https://doi.org/10.1086/302683.
Mazor M, Alkrinawi S, Chalifa-Caspi V, Manor E, Sheffield VC, Aviram M, et al. Primary ciliary dyskinesia caused by homozygous mutation in DNAL1, encoding dynein light chain 1. Am J Hum Genet. 2011;88(5):599–607. https://doi.org/10.1016/j.ajhg.2011.03.018.
Duriez B, Duquesnoy P, Escudier E, Bridoux AM, Escalier D, Rayet I, et al. A common variant in combination with a nonsense mutation in a member of the thioredoxin family causes primary ciliary dyskinesia. Proc Natl Acad Sci U S A. 2007;104(9):3336–41. https://doi.org/10.1073/pnas.0611405104.
Duquesnoy P, Escudier E, Vincensini L, Freshour J, Bridoux AM, Coste A, et al. Loss-of-function mutations in the human ortholog of Chlamydomonas reinhardtii ODA7 disrupt dynein arm assembly and cause primary ciliary dyskinesia. Am J Hum Genet. 2009;85(6):890–6. https://doi.org/10.1016/j.ajhg.2009.11.008.
WHO. WHO Laboratory Manual for the Examination and Processing of Human Semen. Fifth ed; 2010.
Kruger TF, DuToit TC, Franken DR, Acosta AA, Oehninger SC, Menkveld R, et al. A new computerized method of reading sperm morphology (strict criteria) is as efficient as technician reading. Fertil Steril. 1993;59(1):202–9.
Kruger TF, Ackerman SB, Simmons KF, Swanson RJ, Brugo SS, Acosta AA. A quick, reliable staining technique for human sperm morphology. Arch Androl. 1987;18(3):275–7.
Pang M, Liu Y, Hou X, Yang J, He X, Hou N, et al. A novel APC mutation identified in a large Chinese family with familial adenomatous polyposis and a brief literature review. Mol Med Rep. 2018;18(2):1423–32.
Fowkes ME, Mitchell DR. The role of preassembled cytoplasmic complexes in assembly of flagellar dynein subunits. Mol Biol Cell. 1998;9(9):2337–47.
Badano JL, Mitsuma N, Beales PL, Katsanis N. The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet. 2006;7:125–48.
Paff T, Kooi IE, Moutaouakil Y, Riesebos E, Sistermans EA, Daniels H, et al. Diagnostic yield of a targeted gene panel in primary ciliary dyskinesia patients. Hum Mutat. 2018;39(5):653–65.
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Sun, M., Zhang, Y., JiyunYang et al. Novel compound heterozygous DNAAF2 mutations cause primary ciliary dyskinesia in a Han Chinese family. J Assist Reprod Genet 37, 2159–2170 (2020). https://doi.org/10.1007/s10815-020-01859-7
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DOI: https://doi.org/10.1007/s10815-020-01859-7