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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 11 4013-4018
Copyright © 2000 by The Endocrine Society

From the Clinical Research Centers

Insulin-like 3/Relaxin-Like Factor Gene Mutations Are Associated with Cryptorchidism1

Marlah Tomboc, Peter A. Lee, Mohamed F. Mitwally, Francis X. Schneck, Mark Bellinger and Selma F. Witchel

Division of Pediatric Endocrinology (M.T., M.F.M. S.F.W.), Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; Department of Pediatrics (P.A.L.), Pennsylvania State University School of Medicine, Hershey, Pennsylvania; and Department of Urological Surgery (F.S., M.B.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Address all correspondence and requests for reprints to: Selma F. Witchel, M.D., Division of Pediatric Endocrinology, Children’s Hospital of Pittsburgh, University of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, Pennsylvania 15213. E-mail: witches{at}chplink.chp.edu

Cryptorchidism is a common anomaly of male sexual differentiation. Two phases of testicular descent are recognized, transabdominal and inguinoscrotal. With evidence that androgens and Müllerian inhibitory hormone were not completely responsible for testicular descent, the existence of a third testicular hormone mediating testicular descent was postulated. Insulin-like 3 (INSL3) [also known as relaxin-like factor (RLF) and Leydig insulin-like protein (LEY I-L)] is a member of the insulin/relaxin hormone superfamily that is highly expressed in Leydig cells. The phenotype of transgenic mice with targeted deletion of the Insl3 gene was bilateral cryptorchidism with morphological evidence of abnormal gubernacular development. With this implicit evidence that Insl3 mediates testicular descent in mice, we performed mutation detection analysis of the coding regions of the 2 exon INSL3 gene in genomic DNA samples obtained from 145 formerly cryptorchid patients and 36 adult male controls. Single-strand conformational polymorphism analysis was used for the mutation detection studies. Two mutations, R49X and P69L, and several polymorphisms were identified. Both mutations were located in the connecting peptide region of the protein. The frequency of INSL3/RLF gene mutations as a cause of cryptorchidism is low, because only 2 of 145 (1.4%) formerly cryptorchid patients were found to have mutations.




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