title: Understanding the molecular mechanisms of human microtia via a pig model of HOXA1 syndrome.
abstract: Microtia is a congenital malformation of the outer ears. Although both genetic and environmental components have been implicated in microtia, the genetic causes of this innate disorder are poorly understood. Pigs have naturally occurring diseases comparable to those in humans, providing exceptional opportunity to dissect the molecular mechanism of human inherited diseases. Here we first demonstrated that a truncating mutation in HOXA1 causes a monogenic disorder of microtia in pigs. We further performed RNA sequencing (RNA-Seq) analysis on affected and healthy pig embryos (day 14.25). We identified a list of 337 differentially expressed genes (DEGs) between the normal and mutant samples, shedding light on the transcriptional network involving HOXA1. The DEGs are enriched in biological processes related to cardiovascular system and embryonic development, and neurological, renal and urological diseases. Aberrant expressions of many DEGs have been implicated in human innate deformities corresponding to microtia-associated syndromes. After applying three prioritizing algorithms, we highlighted appealing candidate genes for human microtia from the 337 DEGs. We searched for coding variants of functional significance within six candidate genes in 147 microtia-affected individuals. Of note, we identified one EVC2 non-synonymous mutation (p.Asp1174Asn) as a potential disease-implicating variant for a human microtia-associated syndrome. The findings advance our understanding of the molecular mechanisms underlying human microtia, and provide an interesting example of the characterization of human disease-predisposing variants using pig models.
authors.affiliation: Key Laboratory for Animal Biotechnology of Jiangxi Province and the Ministry of Agriculture of China, Jiangxi Agricultural University, Nanchang 330045, People's Republic of China College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou 450002, People's Republic of China.
authors.forename: Ruimin
authors.initials: R
authors.lastname: Qiao
authors.affiliation: Key Laboratory for Animal Biotechnology of Jiangxi Province and the Ministry of Agriculture of China, Jiangxi Agricultural University, Nanchang 330045, People's Republic of China.
authors.forename: Yuyong
authors.initials: Y
authors.lastname: He
authors.affiliation: Plastic Surgery Hospital, Peking Union Medical College, Beijing 100144, People's Republic of China.
authors.forename: Bo
authors.initials: B
authors.lastname: Pan
authors.affiliation: Key Laboratory for Animal Biotechnology of Jiangxi Province and the Ministry of Agriculture of China, Jiangxi Agricultural University, Nanchang 330045, People's Republic of China.
authors.forename: Shijun
authors.initials: S
authors.lastname: Xiao
authors.affiliation: Key Laboratory for Animal Biotechnology of Jiangxi Province and the Ministry of Agriculture of China, Jiangxi Agricultural University, Nanchang 330045, People's Republic of China.
authors.forename: Xufei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Laboratory for Animal Biotechnology of Jiangxi Province and the Ministry of Agriculture of China, Jiangxi Agricultural University, Nanchang 330045, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Key Laboratory for Animal Biotechnology of Jiangxi Province and the Ministry of Agriculture of China, Jiangxi Agricultural University, Nanchang 330045, People's Republic of China.
authors.forename: Zhiyan
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Key Laboratory for Animal Biotechnology of Jiangxi Province and the Ministry of Agriculture of China, Jiangxi Agricultural University, Nanchang 330045, People's Republic of China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Hong
authors.affiliation: Key Laboratory for Animal Biotechnology of Jiangxi Province and the Ministry of Agriculture of China, Jiangxi Agricultural University, Nanchang 330045, People's Republic of China.
authors.forename: Yuyun
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Key Laboratory for Animal Biotechnology of Jiangxi Province and the Ministry of Agriculture of China, Jiangxi Agricultural University, Nanchang 330045, People's Republic of China renjunjxau@hotmail.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000465:Algorithms; D000818:Animals; D065817:Congenital Microtia / Q000235:genetics*; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005808:Genes, Recessive; D056726:Genetic Association Studies; D056426:Genetic Loci; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D034421:Sus scrofa; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000099261:Homeobox A1 Protein
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; D000099261:Homeobox A1 Protein
keywords: EVC2; HOXA1; Microtia; Molecular mechanism; Pig model