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


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.


CONCLUSIONS
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.
Kalfa
Nicolas
N
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, USA.
Liu
Benchun
B
Klein
Ophir
O
Ophir
Klein
K
Audran
Francoise
F
Wang
Ming-Hsieh
MH
Mei
Cao
C
Sultan
Charles
C
Baskin
Laurence S
LS
D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D006801:Humans; D007021:Hypospadias / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017434:Protein Structure, Tertiary; D012720:Severity of Illness Index; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*
D004268:DNA-Binding Proteins; C528016:MAMLD1 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors