Associations between DNAH1 gene polymorphisms and male infertility

Abstract

Genetic abnormalities could account for 10% to 15% of male infertility cases, so increasing attention is being paid to gene mutations in this context. DNAH1 gene polymorphisms are highly correlated with astheno-teratozoospermia, but limited information has been reported on pathogenic variations in DNAH1 in the Chinese population. We explored 4 novel variations of the DNAH1 gene in Chinese infertile patients. Mutation screening of the DNAH1 gene was performed on 87 cases of asthenozoospermia with targeted high-throughput sequencing technology; another 200 nonobstructive azoospermia cases were further analyzed to investigate the prevalence of DNAH1 variations. The effects of the variations on protein function were further assessed by bioinformatic prediction. For carriers of DNAH1 variations, genetic counseling should be considered. Assisted reproductive technologies should be performed for these individuals and microsurgery should be considered for patients with azoospermia. DNAH1 variations were identified in 6 of 287 patients. These included 8 heterozygous variations in exons and a splicing site. Among these, 4 variations (g.52400764G>C, g.52409336C>T, g.52430999_52431000del, g.52412624C>A) had already been registered in the 1000 Genomes and Exome Aggregation Consortium databases. The other 4 novel variations (g.52418050del, g.52404762T>G, g.52430536del, g.52412620del) were all predicted to be pathogenic by in silico analysis. The variations g.52418050del and g.52430999_52431000del were detected in 1 patient who was more severe than another patient with the variation g.52430999_52431000del. Physicians should be aware of genetic variants in male infertility patients and DNAH1 mutations should be considered in patients with asthenospermia or azoospermia.

Novel bi-allelic mutations in DNAH1 cause multiple morphological abnormalities of the sperm flagella resulting in male infertility

“…In 2001, asthenozoospermia owing to DNAH1 mutations were identified (4). MMAF became a recognized disorder in 2014, and several pathogenic variants of DNAH1 associated with sperm flagella development were recognized as potential contributors to MMAF (5,7,(21)(22)(23)(24). We identified bi-allelic loss-of-function mutations in DNAH1 from an infertile male with MMAF by WES.…”

“…This severely damaged the dynein heavy chain domain at the c-terminal of the protein and the tertiary structure of DNAH1, resulting in its dysfunction (23). Three asthenoteratozoospermia patients, 2.09% of the patients tested using bioinformatics analyses, carried four pathogenic DNAH1 variants (5). The other two mutations were missense mutations, which were c. 6446T>G (g. 52404762T>G) and c. 7205C>A (g. 52412624C>A), may adversely affect protein function (5).…”

“…Developmental disturbances may be responsible for abnormalities in mitochondrial sheath, failure of the flagella to properly elongate, and the characteristic absence of CPs in MMAF with patients. The development of MMAF has been linked to many genes, including CFAP65, CFAP44, CFAP43, CFAP69, DNAH1, CFAP251, AK7, CEP135, QRICH2, FSIP2, TTC21A, SPEF2, ARMC2, WDR66, AKAP4, and CCDC39 (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). However, known genetic defects account for only 60% of patients with MMAF.…”

A novel frameshift mutation in ubiquitin-specific protease 26 gene in a patient with severe oligozoospermia

“…An in-house targeted gene panel (Beijing Medriv Academy of Genetics and Reproduction, Beijing, P. R. China), including USP26, was sequenced on the Illumina MiSeq platform (Illumina, San Diego, CA, U.S.A.). Selected targeted next-generation sequencing and data analysis were performed as described previously [15]. In brief, peripheral blood DNA samples were extracted using a DNA extraction kit (Beijing Tiangen Biotech Co., Ltd., China), and then the target gene panel was sequenced from the DNA sample using the Illumina MiSeq platform.…”

Research Progress of Male Reproductive Toxicity of Chinese Materia Medicas

“…Colchicine, an alkaloid originally extracted from the liliaceous plant meadow saffron, can be used in the treatment of acute attacks of gouty arthritis to prevent joint damage caused by urate. Colchicine [66] cannot only inhibit sperms' motility, induce sperms' apoptosis, but also reduce the secretion of serum testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH). Infertility happens when reproductive-related hormones are at abnormal level.…”