Common genetic variation in KATNAL1 non-coding regions is involved in the susceptibility to severe phenotypes of male infertility
Por:
Cervan-Martin, M, Bossini-Castillo, L, Guzman-Jimenez, A, Rivera-Egea, R, Garrido, N, Lujan, S, Romeu, G, Santos-Ribeiro, S, Castilla, JA, Gonzalvo, MD, Clavero, A, Maldonado, V, Vicente, FJ, Burgos, M, Jimenez, R, Gonzalez-Munoz, S, Sanchez-Curbelo, J, Lopez-Rodrigo, O, Pereira-Caetano, I, Marques, PI, Carvalho, F, Barros, A, Bassas, L, Seixas, S, Goncalves, J, Larriba, S, Lopes, AM, Palomino-Morales, RJ, Carmona, FD
Publicada:
1 oct 2022
Ahead of Print:
1 jul 2022
Resumen:
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.
Filiaciones:
Cervan-Martin, M:
Univ Granada, Ctr Invest Biomed, Dept Genet, Granada, Spain
Univ Granada, Ctr Invest Biomed, Inst Biotecnol, Granada, Spain
Inst Invest Biosanitaria Ibs Granada, Granada, Spain
Bossini-Castillo, L:
Univ Granada, Ctr Invest Biomed, Dept Genet, Granada, Spain
Univ Granada, Ctr Invest Biomed, Inst Biotecnol, Granada, Spain
Inst Invest Biosanitaria Ibs Granada, Granada, Spain
Guzman-Jimenez, A:
Univ Granada, Ctr Invest Biomed, Dept Genet, Granada, Spain
Univ Granada, Ctr Invest Biomed, Inst Biotecnol, Granada, Spain
Inst Invest Biosanitaria Ibs Granada, Granada, Spain
Rivera-Egea, R:
IVIRMA Valencia, Androl Lab, Valencia, Spain
IVIRMA Valencia, Sperm Bank, Valencia, Spain
IVI Fdn, Inst Invest Sanitaria La Fe IIS La Fe, Valencia, Spain
Garrido, N:
IVI Fdn, Inst Invest Sanitaria La Fe IIS La Fe, Valencia, Spain
Hosp Univ, Serv Urol, Valencia, Spain
Politecn La Fee Inst Invest Sanitaria La Fe IIS L, Valencia, Spain
Lujan, S:
Hosp Univ, Serv Urol, Valencia, Spain
Politecn La Fee Inst Invest Sanitaria La Fe IIS L, Valencia, Spain
Romeu, G:
Hosp Univ, Serv Urol, Valencia, Spain
Politecn La Fee Inst Invest Sanitaria La Fe IIS L, Valencia, Spain
Santos-Ribeiro, S:
IVI RMA Lisbon, Lisbon, Portugal
Univ Lisbon, Fac Med, Dept Obstet & Gynecol, Lisbon, Portugal
Castilla, JA:
Inst Invest Biosanitaria Ibs Granada, Granada, Spain
HU Virgen Nieves, UGC Obstetricia & Ginecol, Unidad Reprod, Granada, Spain
CEIFER GAMETIA Biobank, Granada, Spain
Gonzalvo, MD:
Inst Invest Biosanitaria Ibs Granada, Granada, Spain
HU Virgen Nieves, UGC Obstetricia & Ginecol, Unidad Reprod, Granada, Spain
Clavero, A:
Inst Invest Biosanitaria Ibs Granada, Granada, Spain
HU Virgen Nieves, UGC Obstetricia & Ginecol, Unidad Reprod, Granada, Spain
Maldonado, V:
Complejo Hosp Jaen, UGC Obstetricia & Ginecol, Jaen, Spain
Vicente, FJ:
Inst Invest Biosanitaria Ibs Granada, Granada, Spain
HU Virgen de las Nieves, UGC Urol, Granada, Spain
Burgos, M:
Univ Granada, Ctr Invest Biomed, Dept Genet, Granada, Spain
Univ Granada, Ctr Invest Biomed, Inst Biotecnol, Granada, Spain
Jimenez, R:
Univ Granada, Ctr Invest Biomed, Dept Genet, Granada, Spain
Univ Granada, Ctr Invest Biomed, Inst Biotecnol, Granada, Spain
Gonzalez-Munoz, S:
Univ Granada, Ctr Invest Biomed, Dept Genet, Granada, Spain
Univ Granada, Ctr Invest Biomed, Inst Biotecnol, Granada, Spain
Inst Invest Biosanitaria Ibs Granada, Granada, Spain
Sanchez-Curbelo, J:
Fundacio Puigvert, Lab Seminol & Embryol, Androl Serv, Barcelona, Spain
Lopez-Rodrigo, O:
Fundacio Puigvert, Lab Seminol & Embryol, Androl Serv, Barcelona, Spain
Pereira-Caetano, I:
Inst Nacl Saude Dr Ricardo Jorge, Dept Genet Humana, Lisbon, Portugal
Marques, PI:
Univ Porto 13S, Inst Invest & Inovacao Saude, Porto, Portugal
Univ Porto IPATIMUP, Inst Mol Pathol & Immunol, Porto, Portugal
Carvalho, F:
Univ Porto 13S, Inst Invest & Inovacao Saude, Porto, Portugal
Univ Porto, Dept Patol, Serv Genet, Fac Med, Porto, Portugal
Barros, A:
Univ Porto 13S, Inst Invest & Inovacao Saude, Porto, Portugal
Univ Porto, Dept Patol, Serv Genet, Fac Med, Porto, Portugal
Bassas, L:
Fundacio Puigvert, Lab Seminol & Embryol, Androl Serv, Barcelona, Spain
Seixas, S:
Univ Porto 13S, Inst Invest & Inovacao Saude, Porto, Portugal
Univ Porto IPATIMUP, Inst Mol Pathol & Immunol, Porto, Portugal
Goncalves, J:
Inst Nacl Saude Dr Ricardo Jorge, Dept Genet Humana, Lisbon, Portugal
Nova Med Sch, Tox Ctr Toxicogenom & Saude Humana, Lisbon, Portugal
Larriba, S:
Bellvitge Biomed Res Inst IDIBELL, Human Mol Genet Grp, Barcelona, Spain
Lopes, AM:
Univ Porto 13S, Inst Invest & Inovacao Saude, Porto, Portugal
Univ Porto IPATIMUP, Inst Mol Pathol & Immunol, Porto, Portugal
Palomino-Morales, RJ:
Inst Invest Biosanitaria Ibs Granada, Granada, Spain
Univ Granada, Dept Bioquim & Biol Mol 1, Granada, Spain
Carmona, FD:
Univ Granada, Ctr Invest Biomed, Dept Genet, Granada, Spain
Univ Granada, Ctr Invest Biomed, Inst Biotecnol, Granada, Spain
Inst Invest Biosanitaria Ibs Granada, Granada, Spain
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