Molecular Human Reproduction, Vol. 9, No. 2, 61-68,
February 2003
© 2003 European Society of Human Reproduction and Embryology
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Microsatellite instability and defects in mismatch repair proteins: a new aetiology for Sertoli cell-only syndrome
Submitted on May 24, 2002; resubmitted on September 9, 2002. accepted on November 18, 2002
1 Molecular and Cellular Biology Department and 2 Scott Department of Urology, Baylor College of Medicine, Houston, TX 77030, USA, 3 Clinic of Urology, University Hospital, Basel, 4031, Switzerland, 4 Department of Urology, University of Tennessee School of Medicine, TN 37920, USA, 5 Departement de Genetique Medicale and Inserm U491, Genetique Medicale et Developpement, Campus de la Timone, Marseille, 13385, France and 6 Division of Andrology, University of Illinois at Chicago, IL 60612, USA
7 To whom correspondence should be addressed. e-mail: dlamb{at}bcm.tmc.edu
Microsatellite instability is characteristic of certain types of cancer, and is present in rodents lacking specific DNA mismatch repair proteins. These azoospermic mice exhibit spermatogenic defects similar to some human testicular failure patients. Therefore, we hypothesized that microsatellite instability due to deficiencies in mismatch repair genes might be an unrecognized aetiology of human testicular failure. Because these azoospermic patients are candidates for testicular sperm extraction and ICSI, transmission of mismatch repair defects to the offspring is possible. Seven microsatellite loci were analysed for instability in specimens from 41 testicular failure patients and 20 controls. Blood and testicular DNA were extracted from patient and control specimens, and amplified by PCR targeting seven microsatellite loci. DNA fragment length was analysed with an ABI Prism 310 Genotyping Machine and GeneScan software. Immunohistochemistry was performed on paraffinized testis biopsy sections and cultured testicular fibroblasts from each patient to determine if expression of the mismatch repair proteins hMSH2 and hMLH1 was normal in both somatic and germline cells. Results demonstrate that microsatellite instability and DNA mismatch repair protein defects are present in some azoospermic men, predominantly in Sertoli cell-only patients (P < 0.01 and P < 0.05 respectively). This provides evidence of a previously unrecognized aetiology of testicular failure that may be associated with cancer predisposition.
Key words: azoospermic/ICSI/microsatellite instability/mismatch repair proteins/Sertoli cell-only
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