Browsing by Author "Marques, Patricia Isabel"
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- Common genetic variation in KATNAL1 non-coding regions is involved in the susceptibility to severe phenotypes of male infertilityPublication . Cerván‐Martín, Miriam; Bossini‐Castillo, Lara; Guzmán‐Jiménez, Andrea; Rivera‐Egea, Rocío; Garrido, Nicolás; Lujan, Saturnino; Romeu, Gema; Santos‐Ribeiro, Samuel; Castilla, José Antonio; Gonzalvo, María del Carmen; Clavero, Ana; Maldonado, Vicente; Vicente, Francisco Javier; Burgos, Miguel; Jiménez, Rafael; González‐Muñoz, Sara; Sánchez‐Curbelo, Josvany; López‐Rodrigo, Olga; Pereira‐Caetano, Iris; Marques, Patricia Isabel; Carvalho, Filipa; Barros, Alberto; Bassas, Lluís; Seixas, Susana; Gonçalves, João; Larriba, Sara; Lopes, Alexandra Manuel; Palomino‐Morales, Rogelio Jesús; Carmona, Francisco DavidBackground: 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.
- Common Variation in the PIN1 Locus Increases the Genetic Risk to Suffer from Sertoli Cell-Only SyndromePublication . Cerván-Martín, Miriam; Bossini-Castillo, Lara; Guzmán-Jimenez, Andrea; Rivera-Egea, Rocío; Garrido, Nicolás; Luján, Saturnino; Romeu, Gema; Santos-Ribeiro, Samuel; Castilla, José A.; Gonzalvo, M. Carmen; Clavero, Ana; Vicente, F. Javier; Maldonado, Vicente; González-Muñoz, Sara; Rodríguez-Martín, Inmaculada; Burgos, Miguel; Jiménez, Rafael; Pinto, Maria Graça; Pereira, Isabel; Nunes, Joaquim; Sánchez-Curbelo, Josvany; López-Rodrigo, Olga; Pereira-Caetano, Iris; Marques, Patricia Isabel; Carvalho, Filipa; Barros, Alberto; Bassas, Lluís; Seixas, Susana; Gonçalves, João; Larriba, Sara; Lopes, Alexandra M.; Carmona, F. David; Palomino-Morales, Rogelio J.We aimed to analyze the role of the common genetic variants located in the PIN1 locus, a relevant prolyl isomerase required to control the proliferation of spermatogonial stem cells and the integrity of the blood-testis barrier, in the genetic risk of developing male infertility due to a severe spermatogenic failure (SPGF). Genotyping was performed using TaqMan genotyping assays for three PIN1 taggers (rs2287839, rs2233678 and rs62105751). The study cohort included 715 males diagnosed with SPGF and classified as suffering from non-obstructive azoospermia (NOA, n = 505) or severe oligospermia (SO, n = 210), and 1058 controls from the Iberian Peninsula. The allelic frequency differences between cases and controls were analyzed by the means of logistic regression models. A subtype specific genetic association with the subset of NOA patients classified as suffering from the Sertoli cell-only (SCO) syndrome was observed with the minor alleles showing strong risk effects for this subset (ORaddrs2287839 = 1.85 (1.17-2.93), ORaddrs2233678 = 1.62 (1.11-2.36), ORaddrs62105751 = 1.43 (1.06-1.93)). The causal variants were predicted to affect the binding of key transcription factors and to produce an altered PIN1 gene expression and isoform balance. In conclusion, common non-coding single-nucleotide polymorphisms located in PIN1 increase the genetic risk to develop SCO.
- Contribution of TEX15 genetic variants to the risk of developing severe non-obstructive oligozoospermiaPublication . Guzmán-Jiménez, Andrea; González-Muñoz, Sara; Cerván-Martín, Miriam; Rivera-Egea, Rocío; Garrido, Nicolás; Luján, Saturnino; Santos-Ribeiro, Samuel; Castilla, José A.; Gonzalvo, M. Carmen; Clavero, Ana; Vicente, F. Javier; Maldonado, Vicente; Villegas-Salmerón, Javier; Burgos, Miguel; Jiménez, Rafael; Pinto, Maria Graça; Pereira, Isabel; Nunes, Joaquim; Sánchez-Curbelo, Josvany; López-Rodrigo, Olga; Pereira-Caetano, Iris; Marques, Patricia Isabel; Carvalho, Filipa; Barros, Alberto; Bassas, Lluís; Seixas, Susana; Gonçalves, João; Lopes, Alexandra M.; Larriba, Sara; Palomino-Morales, Rogelio J.; Carmona, F. David; Bossini-Castillo, LaraBackground: Severe spermatogenic failure (SPGF) represents one of the most relevant causes of male infertility. This pathological condition can lead to extreme abnormalities in the seminal sperm count, such as severe oligozoospermia (SO) or non-obstructive azoospermia (NOA). Most cases of SPGF have an unknown aetiology, and it is known that this idiopathic form of male infertility represents a complex condition. In this study, we aimed to evaluate whether common genetic variation in TEX15, which encodes a key player in spermatogenesis, is involved in the susceptibility to idiopathic SPGF. Materials and Methods: We designed a genetic association study comprising a total of 727 SPGF cases (including 527 NOA and 200 SO) and 1,058 unaffected men from the Iberian Peninsula. Following a tagging strategy, three tag single-nucleotide polymorphisms (SNPs) of TEX15 (rs1362912, rs323342, and rs323346) were selected for genotyping using TaqMan probes. Case-control association tests were then performed by logistic regression models. In silico analyses were also carried out to shed light into the putative functional implications of the studied variants. Results: A significant increase in TEX15-rs1362912 minor allele frequency (MAF) was observed in the group of SO patients (MAF = 0.0842) compared to either the control cohort (MAF = 0.0468, OR = 1.90, p = 7.47E-03) or the NOA group (MAF = 0.0472, OR = 1.83, p = 1.23E-02). The genotype distribution of the SO population was also different from those of both control (p = 1.14E-02) and NOA groups (p = 4.33–02). The analysis of functional annotations of the human genome suggested that the effect of the SO-associated TEX15 variants is likely exerted by alteration of the binding affinity of crucial transcription factors for spermatogenesis. Conclusion: Our results suggest that common variation in TEX15 is involved in the genetic predisposition to SO, thus supporting the notion of idiopathic SPGF as a complex trait.