1. ¹National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, CAMS & PUMC, Beijing, China
2. ²Plastic Surgery Hospital, CAMS & PUMC, Beijing, China
3. ³Chinese National Human Genome Center, Beijing, China

Correspondence: Professor Y Shen, National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, CAMS & PUMC, 5 Dong Dan San Tiao, Beijing, 100005, China. Tel: +86 10 65296486; Fax: +86 10 65263392; E-mail: sheny@ms.imicams.ac.cn

⁴These authors contributed equally to this work.

Received 27 March 2006; Revised 14 August 2006; Accepted 23 August 2006; Published online 27 September 2006.

Abstract

Hypospadias, one of the most common congenital abnormalities of the male external genitalia with elusive etiology, are caused by a defect in the normal development of the urethra, foreskin and ventral aspect of the penis. Evidences indicate that BMP4 and BMP7, two of those major factors in a signaling cascade involved in controlling the embryonic urethral development, play central roles in the normal development of the urethra, and that HOXA4 and HOXB6 play important roles in the development of skin in various tissues at the time course of the urethral development. We directly sequenced all these exons and exon–intron boundaries of the four genes in 90 unrelated Chinese patients with hypospadias. Thirteen different heterozygous nucleotide variations were identified for the first time in the four genes in 14 of 90 cases. Of the 13 variations, eight are missense: c.619C>G (p.H207D), c.668G>A (p.R223H), c.751C>T (p.H251Y) in BMP4; c.907C>T (p.R303C) in BMP7; c.385G>T (p.G129C), c.869C>G (p.S290C) in HOXA4; c.124C>A (p.P42T), c.367T>C (p.C123R) in HOXB6. None of these variations were found in 380 control chromosomes. Amino-acid sequence alignments showed most of these changed amino acids are conserved across various vertebrate species. In a word, these findings, together with the indicated roles of the four genes, imply that it should not be random events for so many nucleotide variations found in the present study. Further functional studies are required to make the associations clear between these variants and hypospadias.