Common genetic variation in KATNAL1 non‐coding regions is involved in the susceptibility to severe phenotypes of male infertility

Abstract

Background: Previous studies in animal models evidenced that genetic mutations of KATNAL1, resulting in dysfunction of its encoded protein, lead to male infertility through disruption of microtubule remodelling and premature germ cell exfoliation.Subsequent studies in humans also suggested a possible role of KATNAL1 singlenucleotide polymorphisms in the development of male infertility as a consequence of severe spermatogenic failure. Objectives:The main objective of the present study is to evaluate the effect of the common genetic variation of KATNAL1 in a large and phenotypically well-characterised cohort of infertile men because of severe spermatogenic failure. Materials and methods:A total of 715 infertile men because of severe spermatogenic failure, including 210 severe oligospermia and 505 non-obstructive azoospermia patients, as well as 1058 unaffected controls were genotyped for three KATNAL1 single-nucleotide polymorphism taggers (rs2077011, rs7338931 and rs2149971).Case-control association analyses by logistic regression assuming different models and in silico functional characterisation of risk variants were conducted.Results: Genetic associations were observed between the three analysed taggers and different severe spermatogenic failure groups. However, in all cases, the haplotype model (rs2077011*C | rs7338931*T | rs2149971*A) better explained the observed associations than the three risk alleles independently. This haplotype was associated with non-obstructive azoospermia (adjusted p = 4.96E-02, odds ratio = 2.97), Sertolicell only syndrome (adjusted p = 2.83E-02, odds ratio = 5.16) and testicular sperm extraction unsuccessful outcomes (adjusted p = 8.99E-04, odds ratio = 6.13). The in silico analyses indicated that the effect on severe spermatogenic failure predisposition could be because of an alteration of the KATNAL1 splicing pattern.Conclusions: Specific allelic combinations of KATNAL1 genetic polymorphisms may confer a risk of developing severe male infertility phenotypes by favouring the overrepresentation of a short non-functional transcript isoform in the testis.

Deciphering the Molecular Characteristics of Human Idiopathic Nonobstructive Azoospermia from the Perspective of Germ Cells

“…We found that HES7 (Hes family bHLH TF 7), as a transcriptional repressor, [ 52 ] was significantly upregulated in iNOA cells. Another key TF, SOX5, is necessary for correct gene expression patterns during spermatogenesis [ 53 ] and its expression was significantly downregulated in iNOA cells. Therefore, we speculate that the increase in HES7 transcriptional activity and decrease in SOX5 transcriptional activity may disrupt the key regulatory network during spermatogenesis and cause iNOA.…”

A Comprehensive Genetic Study of Microtubule-Associated Gene Clusters for Male Infertility in a Taiwanese Cohort

“…Studies in mutant mice [10] indicate that loss-of-function mutations in KATNAL1 disrupt MT function and can cause male infertility by affecting spermatogenesis. Subsequent human studies [11] also supported that mutations in the KATNAL1 gene may facilitate male infertility. Furthermore, Wu et al [12] also highlighted the importance of MTs-related gene defects (particularly KIF15 and dynamin 1) in azoospermia samples by using single-cell transcriptome analysis (scRNAseq).…”