A novel homozygous frameshift mutation in MNS1 associated with severe oligoasthenoteratozoospermia in humans
Yong Li1, Wei-Li Wang1, Chao-Feng Tu1,2,3, Lan-Lan Meng2,3, Tong-Yao Hu1, Juan Du1,2,3, Ge Lin1,2,3, Hong-Chuan Nie1,2,3, Yue-Qiu Tan1,2,3
1 Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha 410078, China
2 Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410078, China
3 Clinical Research Center for Reproduction and Genetics in Hunan Province, Changsha 410078, China
Correspondence: Dr. YQ Tan (email@example.com) or Dr. HC Nie (firstname.lastname@example.org)
Oligoasthenoteratozoospermia (OAT) refers to the combination of various sperm abnormalities, including a decreased sperm count, reduced motility, and abnormal sperm morphology. Only a few genetic causes have been shown to be associated with OAT. Herein, we identified a novel homozygous frameshift mutation in meiosis-specific nuclear structural 1 (MNS1; NM_018365: c.603_604insG: p.Lys202Glufs*6) by whole-exome sequencing in an OAT proband from a consanguineous Chinese family. Subsequent variant screening identified four additional heterozygous MNS1 variants in 6/219 infertile individuals with oligoasthenospermia, but no MNS1 variants were observed among 223 fertile controls. Immunostaining analysis showed MNS1 to be normally located in the whole-sperm flagella, but was absent in the proband's sperm. Expression analysis by Western blot also confirmed that MNS1 was absent in the proband's sperm. Abnormal flagellum morphology and ultrastructural disturbances in outer doublet microtubules were observed in the proband's sperm. A total of three intracytoplasmic sperm injection cycles were carried out for the proband's wife, but they all failed to lead to a successful pregnancy. Overall, this is the first study to report a loss-of-function mutation in MNS1 causing OAT in a Han Chinese patient.
Keywords: intracytoplasmic sperm injection; male infertility; meiosis-specific nuclear structural 1 (MNS1) ; oligoasthenoteratozoospermia; whole-exome sequencing