title: Analysis of large phenotypic variability of EEC and SHFM4 syndromes caused by K193E mutation of the TP63 gene.
abstract: EEC (ectrodactyly, ectodermal dysplasia, clefting; OMIM 604292) is an autosomal dominant developmental disorder resulting mainly from pathogenic mutations of the DNA-binding domain (DBD) of the TP63 gene. In this study, we showed that K193E mutation in nine affected individuals of a four-generation kindred with a large degree of phenotypic variability causes four different syndromes or TP63-related disorders: EEC, Ectrodactyly-ectodermal dysplasia (EE), isolated ectodermal dysplasia, and isolated Split Hand/Foot Malformation type 4 (SHFM4). Genotype-phenotype and DBD structural modeling analysis showed that the K193-located loop L2-A is associated with R280 through hydrogen bonding interactions, while R280 mutations also often cause large phenotypic variability of EEC and SHFM4. Thus, we speculate that K193 and several other DBD mutation-associated syndromes may share similar pathogenic mechanisms, particularly in the case of the same mutation with different phenotypes. Our study and others also suggest that the phenotypic variability of EEC is attributed, at least partially, to genetic and/or epigenetic modifiers.
authors.affiliation: Department of Oral and Maxillofacial Surgery, School of Stomatology, the Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Wei
authors.forename: Yang
authors.initials: Y
authors.lastname: Xue
authors.forename: Lian
authors.initials: L
authors.lastname: Wu
authors.forename: Jie
authors.initials: J
authors.lastname: Ma
authors.forename: Xiuli
authors.initials: X
authors.lastname: Yi
authors.forename: Junrui
authors.initials: J
authors.lastname: Zhang
authors.forename: Bin
authors.initials: B
authors.lastname: Lu
authors.forename: Chunying
authors.initials: C
authors.lastname: Li
authors.forename: Dashuang
authors.initials: D
authors.lastname: Shi
authors.forename: Songtao
authors.initials: S
authors.lastname: Shi
authors.forename: Xinghua
authors.initials: X
authors.lastname: Feng
authors.forename: Tao
authors.initials: T
authors.lastname: Cai
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D044466:Asian People / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D004247:DNA / Q000378:metabolism; D004252:DNA Mutational Analysis; D004476:Ectodermal Dysplasia / Q000235:genetics*; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D006801:Humans; D017880:Limb Deformities, Congenital / Q000235:genetics*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017434:Protein Structure, Tertiary; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D004247:DNA