Free PMC article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9546047/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 spermato genic 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.This work was supported by the Spanish Ministry of Economy and
Competitiveness through the Spanish National Plan for Scientific
and Technical Research and Innovation (refs. SAF2016-78722-R and
PID2020-120157RB-I00), the ‘Instituto de Salud Carlos III’ (Fondo
de Investigaciones Sanitarias)/Fondo Europeo de Desarrollo Regional
‘Una manera de hacer Europa’ (FIS/FEDER) (ref. DTS18/00101 to
Sara Larriba), the Generalitat de Catalunya (ref. 2017SGR191), the
‘Ramón y Cajal’ program (ref. RYC-2014-16458) and the ‘Juan de
la Cierva Incorporación’ program (ref. IJC2018-038026-I), as well as
the Andalusian Government through the R&D&i Projects Grants for
Universities and Public Research Entities (ref. PY20_00212), which
include FEDER funds. Andrea Guzmán-Jiménez was a recipient of a
grant from the Spanish Ministry of Education and Professional Training (‘Becas de Colaboración en Departamentos Universitarios para el curso académico 2020/2021’). Patricia I. Marques is supported by
the FCT post-doctoral fellowship (SFRH/BPD/120777/2016), financed
from the Portuguese State Budget of the Ministry for Science, Tech nology and High Education and from the European Social Fund,
available through the ‘Programa Operacional do Capital Humano’. João
Gonçalves was partially funded by FCT/MCTES through national funds
attributed to the Centre for Toxicogenomics and Human Health—
ToxOmics (UID/BIM/00009/2016 and UIDB/00009/2020). Sara Larriba is sponsored by the Researchers Consolidation Program (ISCIII
SNS/Dpt. Salut Generalitat de Catalunya) (CES09/020).info:eu-repo/semantics/publishedVersio
