Mutation-dependent effects on mRNA and protein expressions in cultured keratinocytes of Hailey-Hailey disease.
Hailey-Hailey disease (HHD) is a dominantly inherited skin disease caused by mutations in ATP2C1 gene, which encodes secretory pathway Ca(2+) /Mn(2+) -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 Ca(2+) -binding residue may induced conformational change, which leads to defective Ca(2+) 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.
Department of Dermatology, Kurume University School of Medicine, and Kurume University Institute of Cutaneous Cell Biology, Kurume, Japan.
Mitsuhiro
M
Matsuda
Takahiro
T
Hamada
Sanae
S
Numata
Kwesi
K
Teye
Hiromi
H
Okazawa
Shinichi
S
Imafuku
Chika
C
Ohata
Minao
M
Furumura
Takashi
T
Hashimoto
D000368:Aged; D000369:Aged, 80 and over; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002478:Cells, Cultured; D018389:Codon, Nonsense; D003593:Cytoplasm / Q000378:metabolism; D005091:Exons; D017353:Gene Deletion; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016506:Pemphigus, Benign Familial / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism*
D018389:Codon, Nonsense; D012333:RNA, Messenger; C403624:ATP2C1 protein, human; D000252:Calcium-Transporting ATPases; D002118:Calcium
Ca2+; Hailey-Hailey disease; P-type ATPase; keratinocyte; mutation