Mutations in exons 5, 7 and 8 of the human voltage-dependent anion channel type 3 (VDAC3) gene in sperm with low motility

Abstract

Summary Voltage‐dependent anion channels (VDACs1‐3) are pore‐forming proteins located in the outer mitochondrial membrane of various tissues and in human sperm flagella. VDACs are involved in metabolite fluxes between mitochondria and other cell compartments and play a role in the motility of mammalian spermatozoa. VDAC3‐deficient male mice lacking exons 5–8 were reported to be healthy but infertile (Sampson et al., 2001). We analysed mutations in these exons of the human VDAC3 (hVDAC3) gene in spermatozoa of 32 asthenozoospermic patients. Previously, we reported on nucleotide substitution mutations in exon 6 (Asmarinah et al., 2005); now, we continue with the examination of exons 5, 7 and 8. Amplification of the exon fragments of the hVDAC3 gene was carried out by polymerase chain reaction (PCR) using specific primers for each exon followed by sequencing. We found various types of mutations in the examined exons of the hVDAC3 gene, such as deletion and nucleotide substitution in spermatozoa from seven of the 30 asthenozoospermic sperm samples (and unconfirmed insertions in two other ones) but none in spermatozoa from normozoospermic controls. Our preliminary data, although of small numbers investigated, suggest that genetic mutations in the hVDAC3 gene could be an explanation for the aetiology of infertility in these asthenozoospermic patients.

The sodium/proton exchanger SLC9C1 (sNHE) is essential for human sperm motility and fertility

“…More recently, pathogenic variants affecting members of the SLC26 family of anion exchangers, namely SLC26A3 and SLC26A8 ( TAT1 ), were also shown to impair the functionality of the cystic fibrosis transmembrane conductance regulator (CFTR) channel, causing asthenozoospermia, associated with defective capacitation, midpiece and annulus disorganization in the case of SLC26A8 11,40,41 . The voltage‐dependent anion channels VDAC2 and 3 were also identified with pathogenic defects leading to idiopathic asthenozoospermia 9,42 . The specific location of all those ion channels/transporters at the plasma membrane of sperm cells, constitutes an interesting cellular background for potential therapeutic strategies to improve sperm motility in asthenozoospermic men.…”

Sperm Ion Transporters and Channels in Human Asthenozoospermia: Genetic Etiology, Lessons from Animal Models, and Clinical Perspectives

“…Thus, they have been intensively studied in mammalian spermatozoa. A first study reported several variants in the VDAC3 gene that distinguish asthenozoospermic patients from normozoospermic individuals [ 46 , 47 ]. These variants consist of deletions in exons 5 to 8 and missense mutations in exons 6 to 7 (Ile131Leu, Lys171Glu, Asp228Asn), which were not found in control individuals.…”

Prospek Kontrasepsi Pria dalam Pengendalian Pertumbuhan Penduduk melalui Pendekatan Molekular

“…Protein VDAC diketahui berhubungan dengan berbagai proses biologis yang terjadi pada mitokondria seperti metabolisme energi dan apoptosis. 26,27,28 Penelitian dengan metode knock out gene VDAC3 pada ekson 5 -8 pada mencit menunjukan VDAC3 bersifat spesifik sperma dan mampu mempengaruhi motilitas sperma sehingga mencit jantan yang tidak memliliki fragmen gen tersebut menjadi infertil tanpa mengubah struktur testis dan jumlah sperma. 29 Berdasarkan uji hambatan antibodi antiVDAC3 terhadap sperma dapat diketahui bahwa antibodi VDAC3 murni dapat meningkatkan jumlah sperma yang tidak bergerak dan juga dapat menurunkan kecepatan pergerakan sperma normal.…”