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

This Article Accepted manuscript (PDF) 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 Google Scholar Articles by Kalfa, N. Articles by Baskin, L. PubMed PubMed Citation Articles by Kalfa, N. Articles by Baskin, L.

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

N Kalfa, Pediatric Urology, University of California-San Francisco Children’s Medical Center, San Francisco, 94143 , United States
B Liu, Center for the Study and Treatment of Hypospadias, Department of Urology, University of California San Francisco Children's Medical Center, San Francisco, United States
O Klein, Department of Pediatrics, Division of Medical Genetics, University of California San Francisco, Children's Medical Center, San Francisco, United States
F Audran, Service d'Hormonologie, Hopital Lapeyronie, CHU Montpellier, montpellier, France
M Wang, Center for the Study and Treatment of Hypospadias, Department of Urology, University of California San Francisco Children's Medical Center, San Francisco, United States
M Cao, Center for the Study and Treatment of Hypospadias, Department of Urology, University of California San Francisco Children's Medical Center, San Francisco, United States
C Sultan, Service d'Hormonologie, Hopital Lapeyronie, CHU Montpellier, montpellier, France
L Baskin, Center for the Study and Treatment of Hypospadias, Department of Urology, University of California San Francisco Children's Medical Center, San Francisco, United States

Correspondence: Nicolas Kalfa, Email: nicolaskalfa{at}gmail.com

Abstract

Objective: : Mutations in 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 30 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 PHYRE 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.