Anorectal malformation associated with a mutation in the P63 gene in a family with split hand–foot malformation

• Published in: International journal of colorectal disease Vol. 28; no. 12; pp. 1621 - 1627
• Main Authors: Su, Pengjun, Yuan, Yuhang, Huang, Ying, Wang, Weilin, Zhang, Zhibo
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.12.2013; Springer; Springer Nature B.V
• Subjects: Anal Canal - abnormalities; Anal Canal - embryology; Anorectal Malformations; Anus, Imperforate - genetics; Asian Continental Ancestry Group - genetics; Base Sequence; China; Cloaca - abnormalities; Cloaca - embryology; DNA Mutational Analysis; Embryonic development; Ethylenediaminetetraacetic acid; Exons - genetics; Family; Female; Gastroenterology; Gene mutations; Genes; Genetic aspects; Genetic research; Hepatology; Humans; Internal Medicine; Limb Deformities, Congenital - genetics; Male; Medicine; Medicine & Public Health; Molecular Sequence Data; Mutation - genetics; Original; Original Article; Pedigree; Proctology; Rectum - abnormalities; Rectum - embryology; Sequence Analysis, DNA; Staining and Labeling; Surgery; Transcription Factors - genetics; Tumor Suppressor Proteins - genetics; Split hand–foot malformation; Hindgut/anorectum; Human embryo; Anorectal malformation
• ISSN: 0179-1958; 1432-1262
• DOI: 10.1007/s00384-013-1725-6

Purpose The aims of this study were to identify the mutation gene of a Chinese family with anorectal malformation (ARM) associated with split hand–foot malformation and to determine the spatiotemporal expression of the mutated gene during hindgut and anorectum development in human embryos. Method A Chinese family with intrafamilial clinically variable manifestation was analyzed and primers were designed for exons 3–14 of P63, DLX5, DLX6, DAC, and HOXD13 as candidate genes and direct sequence analysis of the exons was performed. Immunohistochemical study of mutated gene in the hindgut and anorectum of human embryos of 4th–10th weeks was performed. Result Affected individuals were found to have an Arg227Gln P63 gene mutation. From the 4th–10th weeks of gestation of the human embryo, the P63-positive cells were mainly located on the epithelium of the apical urorectal septum, hindgut, and cloacal membrane. After the anorectum ruptured during the 8th week, the P63 remained strongly immunoreactive on the epithelium of the anal canal and urethra, but the mucous membrane of the rectum exhibited no reaction. Conclusions The mutation identified strongly suggests a causal relationship between the ARM phenotype and P63 . The expression of P63 was persistently active during the dynamic and incessant septation of the cloaca and hindgut, suggesting that P63 may play a pivotal role in the morphogenesis of the hindgut and anorectum.