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

Altres ajuts: Fondo Europeo de Desarrollo Regional 'Una manera de hacer Europa' (FIS/FEDER); the Andalusian Government through the R&D&i Projects Grants for Universities and Public Research Entities (ref. PY20_00212); the Portuguese State Budget of the Ministry for Science, Technology and High Education and from the European Social Fund, available through the 'Programa Operacional do Capital Humano' (the FCT post-doctoral fellowship SFRH/BPD/120777/2016); FCT/MCTES through national funds attributed to the Centre for Toxicogenomics and Human Health-ToxOmics (UID/BIM/00009/2016 and UIDB/00009/2020). 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 single-nucleotide 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), Sertoli-cell 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. Conc