PUBLICATIONS

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

Cerván-Martín M, Bossini-Castillo L, Guzmán-Jiménez A, Rivera-Egea R, Garrido N, Lujan S, Romeu G, Santos-Ribeiro S, Group I, Group LC, Castilla JA, Gonzalvo MC, Clavero A, Maldonado V, Vicente FJ, Burgos M, Jiménez R, González-Muñoz S, Sánchez-Curbelo J, López-Rodrigo O, Pereira-Caetano I, Marques PI, Carvalho F, Barros A, Bassas L, Seixas S, Gonçalves J, Larriba S, Lopes AM, Palomino-Morales RJ, Carmona FD
Andrology. 2022 Jun 25. Online ahead of print. 2022 doi: 10.1111/andr.13221

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 single-nucleotide polymorphisms (SNPs) in the development of male infertility as a consequence of severe spermatogenic failure (SpF). 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-characterized cohort of infertile men due to SpF. Materials and methods: A total of 715 infertile men due to SpF, including 210 severe oligospermia and 505 non-obstructive azoospermia (NOA) patients, as well as 1,058 unaffected controls were genotyped for three KATNAL1 SNP taggers (rs2077011, rs7338931, and rs2149971). Case-control association analyses by logistic regression assuming different models and in silico functional characterization of risk variants were conducted. Results: Genetic associations were observed between the three analysed taggers and different SpF groups. However, in all cases, the haplotype model (rs2077011*C | rs7338931*T | rs2149971*A) explained better the observed associations than the three risk alleles independently. This haplotype was associated with NOA (adjusted P=4.96E-02, OR=2.97), Sertoli-cell only syndrome (adjusted P=2.83E-02, OR=5.16), and testicular sperm extraction unsuccessful outcome (adjusted P=8.99E-04, OR=6.13). The in silico analyses evidenced that the effect on SpF predisposition could be due to an alteration of the KATNAL1 splicing pattern. Conclusions: Specific allelic combinations of KATNAL1 genetic polymorphisms may confer risk to develop severe male infertility phenotypes by favouring the overrepresentation of a short non-functional transcript isoform in the testis.