Mutational analyses of UPIIIA, SHH, EFNB2, and HNF1β in persistent cloaca and associated kidney malformations

Abstract

Objectives-'Persistent cloaca' is a severe malformation affecting females in which the urinary, genital and alimentary tracts share a single conduit. Previously, a Uroplakin IIIA (UPIIIA) mutation was reported in one individual with persistent cloaca, and UPIIIA, Sonic Hedgehog (SHH), Ephrin B2 (EFNB2) and Hepatocyte Nuclear Factor 1β (HNF1β) are expressed during the normal development of organs that are affected in this condition. HNF1β mutations have been associated with uterine malformations in humans, and mutations of genes homologous to human SHH or EFNB2 cause persistent cloaca in mice.Patients and Methods-We sought mutations of coding regions of UPIIIA, SHH, EFNB2 and HNF1β genes by direct sequencing in a group of 20 patients with persistent cloaca. Most had associated malformations of the upper renal tract and over half had impaired renal excretory function. The majority of patients had congenital anomalies outside the renal/genital tracts and two had the VACTERL association.Results-Apart from a previously described index case, we failed to find UPIIIA mutations, and no patient had a SHH, EFNB2 or HNF1β mutation.Conclusion-Persistent cloaca is only rarely associated with UPIIIA mutation. Despite the fact that SHH and EFNB2 are appealing candidate genes, based on their expression patterns and mutant mice phenotypes, they were not mutated in these humans with persistent cloaca. Although HNF1β mutations can perturb paramesonephric duct fusion in humans, HNF1β was not mutated in persistent cloaca.

EFNB2 haploinsufficiency causes a syndromic neurodevelopmental disorder

“…Urogenital or anorectal abnormalities associated with deletion 13q are rare; in males, anomalies varies from anal atresia with hypospadias and perineal fistula to distal hypospadias without anorectal abnormalities; in females anal atresia with vaginal fistula has been reported . Our data confirm that EFNB2 could be involved in syndromic forms of anorectal and genitourinary malformations which could explain why no variant in EFNB2 gene were identified in 331 patients with isolated anorectal malformations or in patients with persistent cloaca associated with renal malformations …”

“…28,30 Our data confirm that EFNB2 could be involved in syndromic forms of anorectal and genitourinary malformations which could explain why no variant in EFNB2 gene were identified in 331 patients with isolated anorectal malformations 19 or in patients with persistent cloaca associated with renal malformations. 32 Table 2). CHD observed in family A support the hypothesis that haploinsufficiency of EFNB2 could be involved in CHD, with incomplete penetrance (2/4 affected patients).…”

Genetics of congenital anomalies of the kidney and urinary tract

“…MCDK or VUR) in a minority of these children [76][77][78]. Functionally, UPs account for impermeability of bladder epithelia to water.…”

Analysis of FOXF1 and the FOX gene cluster in patients with VACTERL association

“…Several factors hint that it is not likely that this pathway would be altered at the level of SHH itself. Not only do loss-of-function mutations in SHH cause holoprosencephaly in humans, but multiple studies have shown negative mutation analysis of the SHH gene in patients with VACTERL association features without any signs of holoprosencephaly [1,6,14]. These studies provide a basis for further investigations aimed at downstream targets of the SHH pathway, such as FOXF1 .…”