FISH analysis demonstrated haploinsufficiency of HLXB9, a gene identified in the triad of a presacral mass (teratoma or anterior meningocele), sacral agenesis, and anorectal malformation, which constitutes the Currarino syndrome.
These results also suggest that reductions in BMP4 expression were possibly responsible for dysfunction of the lumbosacral spinal cord during late developmental stages in ARMs fetal rats.
Major genetic aberrations proposed in the pathogenesis of ARM affect members of the Wnt, Hox (homebox) genes, Sonic hedgehog (Shh) and Gli2, Bmp4, Fgf and CDX1 signalling pathways; probable targets of future molecular gene therapy.
Expression of SHH, GLI family zinc finger 2 (GLI2) and BMP4 mRNA in the posterior wall of the terminal rectum in 40 patients with ARMs (15 high-type and 25 low-type) and 10 normal controls was assessed by reverse transcription-polymerase chain reaction.
We examined the associations of ARM with SNPs in GLI2 and BMP4 using DNA samples of the children and associations with previous miscarriages using parental questionnaires.
Moreover, significant decreased mRNA expressions of these androgen-related genes such as sonic hedgehog, Gli2, Gli3, bone morphogenetic protein 4, Wnt5a, Hoxa13, Hoxd13, fibroblast growth factor 10, and fibroblast growth factor receptor 2 were found in terminal rectum of the ARM male pubs.
Major genetic aberrations proposed in the pathogenesis of ARM affect members of the Wnt, Hox (homebox) genes, Sonic hedgehog (Shh) and Gli2, Bmp4, Fgf and CDX1 signalling pathways; probable targets of future molecular gene therapy.
We examined the associations of ARM with SNPs in GLI2 and BMP4 using DNA samples of the children and associations with previous miscarriages using parental questionnaires.
Expression studies in mice suggest that NEUROD2 and RARA, which reside within the newly identified del17q12q21.2 region, are candidate genes for the formation of microcephaly and ARM.
Western blot and real time RT-PCR revealed that Wif1 and β-catenin protein and mRNA expression level was significantly decreased in the ARM groups compared with the normal group on GD14 and GD15 (<i>p</i> < 0.05).
Our findings in the largest reported cohort to date significantly extend the range of reported manifestations associated with PIGV mutations and demonstrate that the severe end of the clinical spectrum presents as a multiple congenital malformation syndrome with a high frequency of Hirschsprung disease, vesicoureteral, and renal anomalies as well as anorectal malformations.
Western blot and real time RT-PCR revealed that Wif1 and β-catenin protein and mRNA expression level was significantly decreased in the ARM groups compared with the normal group on GD14 and GD15 (<i>p</i> < 0.05).
These results indicate that upregulation of MSX2 and downregulation of BCL2 during cloacal development into the rectum and urethra might be related to the ARM development, and MSX2 promoted apoptosis through reduction of BCL2 expression during the development of anorectal development in ARM.
The serum concentration of VA in ARM neonates was lower than that in control neonates (P < 0.0001), and RARα mRNA expression was lower in the rectum specimens from ARM patients than in the colon specimens from a stoma and the rectum specimens from controls (P < 0.05); there was no significant difference between the colon from a stoma and the rectum from controls.
These data revealed that the expression of Wnt3a in ARM embryos was notably reduced, indicating a potential role for Wnt3a in the maldevelopment of the SMC in patients with ARMs.
We reviewed the eight reported cases with proven PIGV mutations and re-defined the phenotypic spectrum associated with PIGV mutations: intellectual disability, the distinct facial gestalt, brachytelephalangy, and hyperphosphatasia are constant features but also anorectal malformations and Hirschsprung disease as well as cleft lip/palate and hearing impairment should be considered as part of the clinical spectrum.