SEPT14 Mutations and Teratozoospermia: Genetic Effects on Sperm Head Morphology and DNA Integrity.

Ya-Yun Wang,Mei-Feng Chen,Ying-Hung Lin,Hui-Ling Lee,Tsung-Hsuan Lai,Pao-Lin Kuo

doi:10.3390/jcm8091297

Abstract

The main objective of this study was to evaluate the potential genetic effects of SEPT14 on male infertility through sequencing the SEPT14 coding region. To address this research gap, 254 men with sperm abnormalities and 116 normozoospermic men were recruited, and the whole-coding regions of SEPT14 were sequenced. Two heterozygous mutations, p.Ala123Thr (3/254 vs. 0/116) and p.Ile333Thr (3/254 vs. 0/116), were identified in these cases. A high percentage of defective sperm heads was found in sperm with mutated SEPT14. Both mutations are highly evolutionarily conserved among vertebrates. The results of a fine morphological and chromatin structural analysis indicated severely malformed sperm heads with abnormal chromatin packaging through transmission electron microscopy and Toluidine blue staining. Compared with controls, high DNA fragmentation was demonstrated in sperm from cases carrying SEPT14 mutations using the comet assay. In addition, these two mutations in SEPT14 affected its polymerization ability in vitro. These data revels that the two SEPT14 missense mutations impaired sperm head morphology and induced DNA damage. Our study suggests that genetic variant of SEPT14 is one of the effects for human sperm formation and male fertility.

Highlights

The c.367G > A mutation was located in exon 4 and caused a substitution of alanine to threonine at position 123 (p.A123T) within the GTP-binding domain of SEPT14 (Figure 1A,B)
All cases carrying SEPT14 mutations presented with teratozoospermia (91.5% ± 2.88% abnormal sperm), and morphological abnormalities were attributed to head defects (90% ± 4%)
We speculated that SEPT14 mutations may disturb the morphology of sperm heads and cause male infertility

Summary

Introduction

One of the major causes of male infertility is teratozoospermia, which is frequently accompanied with sperm DNA defects [4]. Sperm with high levels of DNA damage or abnormal DNA packaging has negative effects on embryo development and pregnancy outcomes, including pregnancy loss, recurrent spontaneous abortion, and lower live birth rates [5,6,7,8,9,10,11]. According to the various levels of sperm nuclear abnormalities, sperm DNA damage can be categorized as follows: (a) Damage to the actual DNA; (b) nuclear-related gene mutation or protein loss causes decreased DNA compaction; and (c) irregular chromatin structure [12,13,14,15]. Only mutations in certain genes have been linked to sperm DNA damage in a clinical aspect (i.e., PROTAMINE, AURKC, SPATA16, PICK1, DPY19L2, and SEPT12) [16,17,18,19]

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