A novel frameshift mutation in DNAH6 associated with male infertility and asthenoteratozoospermia

Fei Huang; Jun Zeng; Dan Liu; Jing Zhang; Boluo Liang; Jingping Gao; Rong Yan; Xiaobo Shi; Jianlin Chen; Wanjuan Song; Hua-Lin Huang

doi:10.3389/fendo.2023.1122004

A novel frameshift mutation in DNAH6 associated with male infertility and asthenoteratozoospermia

Front Endocrinol (Lausanne). 2023 Jun 22:14:1122004. doi: 10.3389/fendo.2023.1122004. eCollection 2023.

Authors

Fei Huang¹, Jun Zeng¹, Dan Liu¹, Jing Zhang¹, Boluo Liang¹, Jingping Gao¹, Rong Yan¹, Xiaobo Shi¹, Jianlin Chen¹, Wanjuan Song¹, Hua-Lin Huang¹

Affiliation

¹ Reproductive Medicine Center, Department of Obstetrics and Gynecology, The Second Xiangya Hospital, Central South University, Changsha, China.

Abstract

Introduction: Asthenoteratozoospermia is one of the most common causes of male infertility. Several genes have been identified as genetic causative factors, but there is a considerable genetic heterogeneity underlying asthenoteratozoospermia. In this study, we performed a genetic analysis of two brothers from a consanguineous Uighur family in China to identify gene mutations causative for asthenoteratozoospermia-related male infertility.

Methods: Two related patients with asthenoteratozoospermia from a large consanguineous family were sequenced by whole-exome sequencing and Sanger sequencing to identify disease-causing genes. Scanning and transmission electron microscopy analysis revealed ultrastructural abnormalities of spermatozoa. Quantitative real-time PCR (qRT-PCR) analysis and immunofluorescence (IF) analysis were used to assess the expression of the mutant messenger RNA (mRNA) and protein.

Results: A novel homozygous frameshift mutation (c.2823dupT, p.Val942Cysfs*21) in DNAH6 was identified in both affected individuals and was predicted to be pathogenic. Papanicolaou staining and electron microscopy revealed multiple morphological and ultrastructural abnormalities of affected spermatozoa. qRT-PCR and IF analysis showed abnormal expression of DNAH6 in affected sperm, probably due to premature termination code and decay of abnormal 3' untranslated region (UTR) region of mRNA. Furthermore, intracytoplasmic sperm injection could achieve successful fertilization in infertile men with DNAH6 mutations.

Discussion: The novel frameshift mutation identified in DNAH6 may contribute to asthenoteratozoospermia. These findings expand the spectrum of genetic mutations and phenotypes associated with asthenoteratozoospermia and may be useful for genetic and reproductive counseling in male infertility.

Keywords: DNAH6; asthenoteratozoospermia; infertility; mutation; premature termination codon; sperm flagella.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Asthenozoospermia* / genetics
Dyneins* / genetics
Frameshift Mutation
Humans
Infertility, Male* / pathology
Male
RNA, Messenger
Semen / metabolism
Sperm Tail / pathology

Substances

RNA, Messenger
DNAH6 protein, human
Dyneins

Grants and funding

This study was funded by the National Natural Science Foundation of China (No. 81501248), the Science and Technology Innovation Program of Hunan Province (2021RC3031), the Scientific Research Program of Hunan Provincial Health Commission (20220503347), and the Open Research Program of Key Laboratory of Regenerative Biology of Chinese Academy of Sciences (KLRB202010).