Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 105, Issue 6, Pages 1168-1181Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2019.10.010
Keywords
-
Categories
Funding
- National Natural Science Foundation of China [31625015, 31521003, 81601340]
- Special Foundation for Development of Science and Technology of Anhui Province [2017070802D150]
- Jiangsu Commission of Health [H2018050]
- Foundation of the Education Department of Anhui Province [KJ2016A370]
- Shanghai Medical Center of Key Programs for Female Reproductive Diseases [2017ZZ01016]
- Shanghai Municipal Science and Technology Major Project [2017SHZDZX01]
Ask authors/readers for more resources
As a type of severe asthenoteratospermia, multiple morphological abnormalities of the flagella (MMAF) are characterized by the presence of immotile spermatozoa with severe flagellar malformations. MMAF is a genetically heterogeneous disorder, and the known MMAF-associated genes can only account for approximately 60% of human MMAF cases. Here we conducted whole-exome sequencing and identified bi-allelic truncating mutations of the TTC29 (tetratricopeptide repeat domain 29) gene in three (3.8%) unrelated cases from a cohort of 80 MMAF-affected Han Chinese men. TTC29 is preferentially expressed in the testis, and TTC29 protein contains the tetratricopeptide repeat domains that play an important role in cilia- and flagella-associated functions. All of the men harboring TTC29 mutations presented a typical MMAF phenotype and dramatic disorganization in axonemal and/or other peri-axonemal structures. Immunofluorescence assays of spermatozoa from men harboring TTC29 mutations showed deficiency of TTC29 and remarkably reduced staining of intraflagellar-transport-complex-B-associated proteins (TTC30A and IFT52). We also generated a TtC29-mutated mouse model through the use of CRISPR-Cas9 technology. Remarkably, TtC29-mutated male mice also presented reduced sperm motility, abnormal flagellar ultrastructure, and male subfertility. Furthermore, intracytoplasmic sperm injections performed for TtC29-mutated mice and men harboring TTC29 mutations consistently acquired satisfactory outcomes. Collectively, our experimental observations in humans and mice suggest that bi-allelic mutations in TTC29, as an important genetic pathogeny, can induce MMAF-related asthenoteratospermia. Our study also provided effective guidance for clinical diagnosis and assisted reproduction treatments.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available