Mutation screening of BMP4, BMP7, HOXA4 and HOXB6 genes in Chinese patients with hypospadias

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 exonintron 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.619C4G (p.H207D), c.668G4A (p.R223H), c.751C4T (p.H251Y) in BMP4; c.907C4T (p.R303C) in BMP7; c.385G4T (p.G129C), c.869C4G (p.S290C) in HOXA4; c.124C4A (p.P42T), c.367T4C (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.

Ectodermal dysplasia-cutaneous syndactyly syndrome maps to chromosome 7p21.1-p14.3

“…Recently, mutations in several genes of HOXA cluster have been implicated in causing human disorders. Chen et al (2007) reported heterozygous sequence variants in the HOXA4 gene in Chinese patients with hypospadias. Two HOX genes, HOXB6 and HOXA4, play important roles in the epidermal development and diVerentiation of various tissues at week 10-17 of gestation (Stelnicki et al 1998;Kömüves et al 2000).…”

Mutation screening of BMP4 and Id2 genes in Chinese patients with congenital ureteropelvic junction obstruction

“…But the low mutation rate (close to 1%) suggests that BMP4 mutations are not the major cause of this disease. Otherwise, since BMP4 has a broad range of functions in controlling multiple organogenetic processes [18,19], BMP4 mutations have been found in several diseases [2,8,35,39]. In particular, the c.485G> A (p.R162Q) mutation had also been detected in a patient with cleft lip [35].…”

Abnormal urethra formation in mouse models of Split-hand/split-foot malformation type 1 and type 4

“…In fact, recent human genetic studies indicated the possible involvement of Bmp7 and Fgf(s) in the development of hypospadias. 41,42 Epithelial differentiation during the UP formation of the embryonic external genitalia (GT) One of the fundamental characters of the GT development is to develop endodermal epithelia along with GT formation, initially as CM and later forming the UP, subsequently the tubular urethra in the male GT.…”