Mutation-dependent effects on mRNA and protein expressions in cultured keratinocytes of Hailey-Hailey disease

• Published in: Experimental dermatology 2014-07, Vol.23 (7), p.514-516
• Main Authors: Matsuda, Mitsuhiro, Hamada, Takahiro, Numata, Sanae, Teye, Kwesi, Okazawa, Hiromi, Imafuku, Shinichi, Ohata, Chika, Furumura, Minao, Hashimoto, Takashi
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Ca2; Calcium - metabolism; Calcium-Transporting ATPases - metabolism; Cells, Cultured; Codon, Nonsense; Cytoplasm - metabolism; Exons; Gene Deletion; Hailey-Hailey disease; Humans; keratinocyte; Keratinocytes - cytology; Keratinocytes - metabolism; Male; Middle Aged; Mutation; P-type ATPase; Pemphigus, Benign Familial - genetics; Pemphigus, Benign Familial - metabolism; Phosphorylation; Protein Structure, Tertiary; RNA, Messenger - metabolism
• ISSN: 0906-6705; 1600-0625
• DOI: 10.1111/exd.12410

Hailey–Hailey disease (HHD) is a dominantly inherited skin disease caused by mutations in ATP2C1 gene, which encodes secretory pathway Ca2+/Mn2+‐ATPase protein 1. The precise mechanism remains unclear. In this study, to understand molecular basis of HHD, we examined expression of mRNA and protein in cultured keratinocytes derived from three HHD patients with different mutations. We showed that reduced expression of mRNA and protein in patient with p.Gln504X, but not in patients with p.Pro307His and c.1308+1G>A. RT‐PCR analysis for patient with c.1308+1G>A revealed in‐frame exon skipping. Reduction of mRNA and protein in p.Gln504X was considered to be caused by nonsense‐mediated mRNA decay. p.Pro307His located adjacent to Ca2+‐binding residue may induced conformational change, which leads to defective Ca2+ transport. In‐frame shorter transcript caused by c.1308+1G>A may have slightly reduced activity, which accounted for mild phenotype of the patient. These results clarified the pathogenic effects of different causative mutations in development of skin lesions.