title: Next-generation sequencing detection and characterization of a heterozygous novel splice junction mutation in the 2B domain of KRT1 in a family with diffuse palmoplantar keratoderma.
abstract: Diffuse palmoplantar keratoderma (DPPK) is an autosomal-dominant genodermatosis characterized by restricted, uniform hyperkeratosis on the palm and sole epidermis. DPPK is normally associated with dominant-negative mutations in the keratin-encoding gene, KRT1. We report a heterozygous novel point mutation in the exon 6 splice donor site of KRT1 (c.1254G>C) by next-generation sequencing, resulting in the formation of two alternative transcripts, which segregates with DPPK in a four-generation Chinese family. This results in both the complete loss of exon 6 and the simultaneous utilization of a novel in-frame splice site 54 bases downstream of the mutation with the subsequent deletion of 42 amino acids and the insertion of 18 amino acids into the protein's 2B domain. This is the first report of a novel splice donor site mutation with aberrant splicing and the formation of two alternative transcripts causing DPPK. This study also demonstrates the value of next-generation sequencing in the identification of novel disease-causing mutations.
authors.affiliation: Department of Cell Biology and Medical Genetics, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Santasree
authors.initials: S
authors.lastname: Banerjee
authors.forename: Yunqing
authors.initials: Y
authors.lastname: Ren
authors.forename: Tianying
authors.initials: T
authors.lastname: Wei
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: Zhou
authors.forename: Ping
authors.initials: P
authors.lastname: Yu
authors.forename: Fenghui
authors.initials: F
authors.lastname: Guan
authors.forename: Xiaonming
authors.initials: X
authors.lastname: Wei
authors.forename: Sheng
authors.initials: S
authors.lastname: Ye
authors.forename: Shaofeng
authors.initials: S
authors.lastname: Yan
authors.forename: Min
authors.initials: M
authors.lastname: Zheng
authors.forename: Michael L
authors.initials: ML
authors.lastname: Raff
authors.forename: Ming
authors.initials: M
authors.lastname: Qi
mesh_terms: D017398:Alternative Splicing; D002681:China; D003599:Cytoskeleton / Q000378:metabolism; D004252:DNA Mutational Analysis; D005091:Exons; D005192:Family Health; D005260:Female; D015894:Genome, Human; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D007438:Introns; D053556:Keratin-1 / Q000235:genetics* / Q000378:metabolism; D007645:Keratoderma, Palmoplantar / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation; D010375:Pedigree; D017434:Protein Structure, Tertiary
chemical_list: C491616:KRT1 protein, human; D053556:Keratin-1
keywords: KRT1; alternative transcripts; diffuse palmoplantar keratoderma; next-generation sequencing; novel splice donor site mutation