Bi-allelic human TEKT3 mutations cause male infertility with oligoasthenoteratozoospermia owing to acrosomal hypoplasia and reduced progressive motility

Abstract

Oligoasthenoteratozoospermia (OAT) can result in male infertility due to reduced sperm motility and abnormal spermatozoan morphology. The Tektins are a family of highly conserved filamentous proteins expressed in the axoneme and associated structures in many different metazoan species. Earlier studies on mice identified Tektin3 (Tekt3) as a testis-enriched gene, and knockout of Tekt3 resulted in asthenozoospermia in the mice. Here, whole exome sequencing of 100 males with asthenozoospermia from unrelated families was performed, followed by Sanger sequencing, leading to the identification of TEKT3 as a candidate gene in two of these patients and their associated family members. In total, three mutations in the TEKT3 gene were identified in both these patients, including one homozygous deletion–insertion mutation (c.543_547delinsTTGAT: p.Glu182*) and one compound heterozygous mutation (c.[548G > A]; [752A > C], p.[(Arg183Gln)]; [(Gln251Pro)]). Both of these mutations resulted in the complete loss of TEKT3 expression. The patients were both found to produce sperm that, although they showed no apparent defects in the flagellar structure, had reduced progressive motility. In contrast to mice, most sperm from these two patients exhibited acrosomal hypoplasia, although this did not prevent the use of the sperm for in vitro fertilization through an ICSI approach. TEKT3 was found to bind to other TEKT proteins, suggesting that these proteins form a complex within human spermatozoa. Overall, these results suggest that a loss of TEKT3 function can contribute to OAT incidence in humans. TEKT3 deficiencies can reduce sperm motility and contribute to severe acrosomal hypoplasia in spermatozoa, compromising their normal function.

Forkhead-associated phosphopeptide binding domain 1 (FHAD1) deficiency impaired murine sperm motility

“…The advent of new gene knockout techniques has enabled detailed research efforts focused on identifying pathogenic genes associated with male infertility. These efforts have revealed that genes such as TEKT3 may be important causes of male infertility in the general population, even though their knockout in mice does not lead to infertility ( Liu et al, 2023 ; Roy et al, 2009 ). These inconsistent phenotypes may be context- or species-specific.…”

Tektin bundle interacting protein, TEKTIP1, functions to stabilize the tektin bundle and axoneme in mouse sperm flagella

“…Zhou et al recently discovered variants in 10 distinct MIPs (FAM166A, CCDC105, TEX37, EFCAB6, EFHC2, FAM166C, MNS1, TEKT1, CFAP45, and CFAP21) associated with a subtype of asthenozoospermia termed MIP-variant-associated asthenozoospermia (MIVA), which is characterized by impaired sperm motility without evident morphological abnormalities [ 11 ]. Furthermore, two homozygous TEKT3 mutations have been recently identified in infertile men with asthenospermia [ 19 ], highlighting the relevance of tektins deficiency to human male infertility. Our animal study suggests that TEKTIP1 is essential for mouse sperm motility and that its deficiency may be a potential genetic cause of human male infertility with MIVA.…”

“…Although Tekt3 -knockout mice exhibit normal male fertility, they produce sperm with reduced motility and increased flagellar structural beading defects [ 18 ]. A recent study identified two homozygous TEKT3 mutations in infertile men with oligo-astheno-teratozoospermia [ 19 ], highlighting the relevance of tektins deficiency to male infertility.…”