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

• Type: Article in International Scientific Journal
• Date: 2022

Authors

Cervan Martin, M (Author) Other; Bossini Castillo, L (Author) Other; Guzman Jimenez, A (Author) Other; Rivera Egea, R (Author) Other; Garrido, N (Author) Other; Lujan, S (Author) Other; Romeu, G (Author) Other; Santos Ribeiro, S (Author) Other; Castilla, JA (Author) Other; Gonzalvo, MD (Author) Other; Clavero, A (Author) Other; Maldonado, V (Author) Other; Vicente, FJ (Author) Other; Burgos, M (Author) Other; Jimenez, R (Author) Other; Gonzalez Munoz, S (Author) Other; Sanchez Curbelo, J (Author) Other; Lopez Rodrigo, O (Author) Other; Pereira Caetano, I (Author) Other; Marques, PI (Author) Other; carvalho, f (Author) FMUP; barros, a (Author) FMUP; Bassas, L (Author) Other; Seixas, S (Author) Other; Goncalves, J (Author) Other; Larriba, S (Author) Other; Alexandra M Lopes (Author) Other; Palomino Morales, RJ (Author) Other; Carmona, FD (Author) Other

Journal

Title: Andrology

Vol. 10

Pages: 1339-1350

ISSN: 2047-2919

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 2 Citations

Scopus - 2 Citations

Other information

Authenticus ID: P-00W-WSW

DOI: 10.1111/andr.13221

Abstract (EN): 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. 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 12