Intronic variation of the SOHLH2 gene confers risk to male reproductive impairment

Our results suggest that an intronic haplotype of SOHLH2, which encodes a transcription factor with essential roles in spermatogenesis, represents a genetic marker of spermatogenic failure.

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VOLUME 114, ISSUE 2, P398-406


Miriam Cerván-Martín, M.Sc., M. Irene Suazo-Sánchez, M.Sc., Rocío Rivera-Egea, Ph.D., Nicolás Garrido, Ph.D., Saturnino Luján, M.D., Ph.D., Gema Romeu, M.D., Samuel Santos-Ribeiro, M.D., Ph.D., José A. Castilla, M.D., Ph.D., M. Carmen Gonzalvo, M.D., Ph.D., Ana Clavero, M.D., Ph.D., F. Javier Vicente, M.D., Ph.D., Vicente Maldonado, M.D., Miguel Burgos, Ph.D., Francisco J. Barrionuevo, Ph.D., Rafael Jiménez, Ph.D., Josvany Sánchez-Curbelo, M.D., Olga López-Rodrigo, Ph.D., M. Fernanda Peraza, M.D., Iris Pereira-Caetano, M.Sc., Patricia I. Marques, Ph.D., Filipa Carvalho, Ph.D., Alberto Barros, Ph.D., Lluís Bassas, M.D., Ph.D., Susana Seixas, Ph.D., João Gonçalves, Ph.D., Sara Larriba, Ph.D., Alexandra M. Lopes, Ph.D., Rogelio J. Palomino-Morales, Ph.D., F. David Carmona, Ph.D., the Lisbon Clinical Group, IVIRMA Group 



To evaluate whether SOHLH2 intronic variation contributes to the genetic predisposition to male infertility traits, including severe oligospermia (SO) and different nonobstructive azoospermia (NOA) clinical phenotypes.


Genetic association study.


Not applicable.


Five hundred five cases (455 infertile patients diagnosed with NOA and 50 with SO) and 1,050 healthy controls from Spain and Portugal.



Main Outcome Measure(s)

Genomic DNA extraction from peripheral blood mononuclear cells, genotyping of the SOHLH2 polymorphisms rs1328626 and rs6563386 using the TaqMan allelic discrimination technology, case-control association analyses using logistic regression models, and exploration of functional annotations in publicly available databases.


Evidence of association was observed for both rs6563386 with SO and rs1328626 with unsuccessful sperm retrieval after testicular sperm extraction (TESE-) in the context of NOA. A dominant effect of the minor alleles was suggested in both associations, either when the subset of patients with the manifestation were compared against the control group (rs6563386/SO: P=.021, odds ratio [OR] = 0.51; rs1328626/TESE-: P=.066, OR = 1.46) or against the group of patients without the manifestation (rs6563386/SO: P=.014, OR = 0.46; rs1328626/TESE-: P=.012, OR = 2.43). The haplotype tests suggested a combined effect of both polymorphisms. In silico analyses evidenced that this effect could be due to alteration of the isoform population.


Our data suggest that intronic variation of SOHLH2 is associated with spermatogenic failure. The genetic effect is likely caused by different haplotypes of rs6563386 and rs1328626, which may predispose to SO or TESE- depending on the specific allelic combination.

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Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders.