Genetic heterogeneity in Van der Woude syndrome: identification of NOL4 and IRF6 haplotype from the noncoding region as candidates in two families

• Published in: Journal of genetics 2018-03, Vol.97 (1), p.275-285
• Main Authors: Kumari, Priyanka, Ali, Akhtar, Singh, Subodh Kumar, Chaurasia, Amit, Raman, Rajiva
• Format: Article
• Language: English
• Subjects: 3' Untranslated regions; Abnormalities, Multiple - genetics; Alternative Splicing - genetics; Animal Genetics and Genomics; Animals; Binding Sites; Biomedical and Life Sciences; Cell Line; Child; Child, Preschool; Chromosomes, Human - genetics; Cleft Lip - genetics; Cleft lip/palate; Cleft Palate - genetics; Cysts - genetics; DNA, Intergenic - genetics; Embryos; Evolutionary Biology; Family; Female; Genetic aspects; Genetic Heterogeneity; Genetic Predisposition to Disease; Genomes; Genomics; Haplotypes; Haplotypes - genetics; Heredity; Humans; Infant; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - metabolism; Introns; Introns - genetics; Life Sciences; Lip - abnormalities; Lip - embryology; Male; Mice; Microbial Genetics and Genomics; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Mutation - genetics; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Palate - embryology; Pedigree; Plant Genetics and Genomics; Primordia; Repressor Proteins - metabolism; Research Article; RNA, Messenger - genetics; RNA, Messenger - metabolism; Transfection
• ISSN: 0022-1333; 0973-7731
• DOI: 10.1007/s12041-018-0903-2

Van der Woude syndrome (VWS) shows an autosomal dominant pattern of inheritance with two known candidate genes, IRF6 and GRHL3 . In this study, by employing genome-wide linkage analyses on two VWS affected families, we report the cosegregation of an intronic rare variant in NOL4 in one family, and a haplotype consisting of three variants in the noncoding region of IRF6 (introns 1, 8 and 3 ′ UTR) in the other family. Using mouse, as well as human embryos as a model, we demonstrate the expression of NOL4 in the lip and palate primordia during their development. Luciferase, as well as miRNA-transfection assays show decline in the expression of mutant NOL4 construct due to the creation of a binding site for hsa-miR-4796-5p. In family 2, the noncoding region IRF6 haplotype turns out to be the candidate possibly by diminishing its IRF6 expression to half of its normal activity. Thus, here we report a new candidate gene ( NOL4 ) and a haplotype of IRF6 for VWS, and highlight the genetic heterogeneity of this disorder in the Indian population.