Jittima Dhitavat, Leonard Dode, Natalie Leslie, Anavaj Sakuntabhai

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Mutations in the Sarcoplasmic/Endoplasmic Reticulum Ca2+ ATPase Isoform Cause Darier's Disease Jittima Dhitavat, Leonard Dode, Natalie Leslie, Anavaj Sakuntabhai Journal of Investigative Dermatology Volume 121, Issue 3, Pages 486-489 (September 2003) DOI: 10.1046/j.1523-1747.2003.12410.x Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Splicing of ATP2A2. (A) Alternate splicing of ATP2A2 transcripts at nucleotide position 2981 in exon 20 gives rise to two distinct isoforms, SERCA2a and SERCA2b. The mutation identified in this family (2993delTG) is indicated (*). Black boxes represent untranslated regions. (B) Model of the human SERCA2 polypeptide. The predicted secondary structure of SERCA2a consists of 10 transmembrane domains and a tetrapeptide tail located in the cytoplasm, whereas the SERCA2b tail comprises 49 amino acids extending into the ER lumen. Journal of Investigative Dermatology 2003 121, 486-489DOI: (10.1046/j.1523-1747.2003.12410.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Pedigree of the family. Men are represented by squares and women by circles. The solid symbols denote the affected individuals. Journal of Investigative Dermatology 2003 121, 486-489DOI: (10.1046/j.1523-1747.2003.12410.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Identification of ATP2A2 mutations. (A) CSGE showed abnormal electrophoretic mobility of exons 19+20 in affected individuals; I.2, II.6, II.11, and III.8 (lanes 1, 4, 6, 9) and normal electrophoretic mobility in unaffected individuals II.2, II.4, II.6C, II.8, and II.10 (lanes 2, 3, 5, 7, and 8). Lanes 10 and 11 are from normal unrelated controls. (B) Direct sequencing of PCR products of exons 19+20 revealed a TG deletion at nucleotide position 2993 (2993delTG) at a heterozygous state. This mutation resulted in a frameshift and downstream premature termination codon at nucleotide position 3091 (PTC+32aa). Journal of Investigative Dermatology 2003 121, 486-489DOI: (10.1046/j.1523-1747.2003.12410.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Immunodetection of the wild-type and the mutant SERCA2b proteins. (A–C) Immunofluorescence analysis: COS-1 cells transfected with wild-type SERCA2b (B), the mutant 2993delTG (C), or the empty vector (A) were processed for indirect immunofluorescence. Bound mouse anti-SERCA2 (A–C) was detected using fluorescein isothiocyanate-conjugated anti-mouse secondary antibody. (D) Western blot analysis: microsomal proteins extracted from COS-1 cells transfected with wild-type SERCA2b, the mutant 2993delTG or the empty vector were analyzed by western blot using mouse anti-SERCA2 antibody followed by anti-mouse secondary antibodies linked to peroxidase, and detected by enhanced chemiluminescent (ECL) blotting. The 212 kDa band corresponds to SERCA2b dimers (Verboomen et al, 1994). Journal of Investigative Dermatology 2003 121, 486-489DOI: (10.1046/j.1523-1747.2003.12410.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions