HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: EJE-08-0085v1 159/4/453    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kalfa, N. Articles by Baskin, L. S Search for Related Content PubMed PubMed Citation Articles by Kalfa, N. Articles by Baskin, L. S

Mutations of CXorf6 are associated with a range of severities of hypospadias

¹ Department of Pediatric Urology, Center for the Study and Treatment of Hypospadias, Children's Medical Center, University of California San Francisco, 400 Parnassus Avenue, A 640, San Francisco, California 94143, USA² Service d'Hormonologie, Hôpital Lapeyronie, CHU Montpellier, Montpellier, France³ Department of Orofacial Sciences and Pediatrics, Institutes of Human Genetics and Regeneration Medicine, University of California San Francisco, San Francisco, California, USA

(Correspondence should be addressed to L S Baskin; Email: lbaskin{at}urology.ucsf.edu)

Objective: Mutations in chromosome X open reading frame 6 (CXorf6), a recently described candidate gene involved in the development of male genitalia, have been found in patients with complex 46,XY disorders of sexual development (46,XY DSD) including micropenis, bifid scrotum, and penoscrotal hypospadias. The objective of this work was to identify genomic variants of CXorf6 in patients with isolated hypospadias, severe or non-severe.

Design and methods: Forty-one patients with glandular to perineal hypospadias and thirty controls were studied. Direct sequencing for coding exons 3–6 of CXorf6 and their flanking splice sites was performed on DNA extracted from foreskin collected from surgery. Secondary and tertiary structures of the protein were predicted using NNpredict and Protein Homology/analogY Recognition Engine engines.

Results: Four mutations (9.7% of cases) were identified. One missense mutation (1295T>C, V432A) and two deletions (325delG, predicted to cause a stop codon L121X) occurred in patients with penoscrotal and proximal hypospadias. One patient with subcoronal hypospadias had CAG-repeat amplification in the second polyglutamine domain of CXorf6. Secondary structure prediction indicated that this insertion occurred in a helix element of the protein. The tertiary structure prediction showed an alteration of the shape of the protein and crowding between domains.

Conclusion: CXorf6 mutations are associated with isolated hypospadias of varying severity. However, the pathophysiology of these mutations and the function of the CXorf6 gene product remain to be investigated.