Journal of Dermatology 2014; 41: 349–370
LETTERS TO THE EDITOR
Novel ATP2A2 mutation in a patient with Darier’s disease Dear Editor, Darier’s disease (Online Mendelian Inheritance in Man no. 124200) is a rare, autosomal dominant genodermatosis in which greasy, yellow to brown, crusted papular lesions develop, mainly in the seborrheic areas of the head, neck and trunk.1 The coalescence of papules produces plaques, which may become papillomatous. Darier’s disease usually presents in the second decade, and the course of the disease is characterized by remissions and relapses. Darier’s disease is inherited with a high penetrance, although the phenotypic expression is variable. The genetic defect was mapped to human chromosome 12q23-q24.1 in 1993.2,3 Subsequently, ATA2A2, which encodes the sarco/endoplasmic reticulum Ca2+-ATPase type 2 isoform, a keratinocyte Ca2+ pump, has been identified as the gene responsible.4 To date, more than 187 pathogenic mutations have been described throughout the gene, including missense, nonsense, substitution, insertion and deletion involving both frame-shift and inframe.5 Here, we report a novel c.1287 + 1 G>T (or IVS10 + 1 G>T) mutation in ATA2A2 in a Japanese woman with Darier’s disease. A 38-year-old woman presented with a 5-year history of firm, rather greasy, harsh papules that were skin colored or brown in seborrheic areas of the trunk (Fig. 1a). As the lesions were itchy, she scratched the tops of the papules causing
(a)
(b)
(c)
(d)
Figure 1. (a) Clinical features of seborrheic areas of the trunk. (b) There are many greasy, red to brown, crusted papules. Fine scales are also observed. (c–d) Histological features (hematoxylin–eosin). (c) Lower and (d) higher magnifications of lesions. (c) Mild acanthosis, elongation of rete ridges, and papillomatosis are present. A thick keratotic plug overlies the lesion. Mild mononuclear cell infiltrates around blood vessels in the dermis are also present. (d) Two characteristic types of dyskeratotic cell, corps ronds (white arrows) and corps grains (green arrows), are observed. Scale bar in (c) = 700 lm.
slight hemorrhage (Fig. 1b). There was no family history of the same skin disease. Histological examination revealed focal acantholysis with corps ronds and corps grains (Fig. 1c,d). No nail or oral mucosa changes were observed. Sun exposure and sweating aggravated her condition. After the application of 5% salicylic acid in petroleum, the lesions improved. She has been followed up at regular intervals at our outpatient clinic. Genomic DNA was extracted from peripheral blood leukocytes for genetic testing after obtaining informed consent. Genomic DNA was polymerase chain reaction amplified for the analysis of exons 1–21 of the ATP2A2 gene and their flanking splice sites. A bidirectional sequence was obtained and the DNA sequence was analyzed and compared to the published gene sequence until the mutation was identified. Sequence analysis of the ATP2A2 gene revealed that the patient was heterozygous for the G>T nucleotide substitution at the +1 position of intron 10. This mutation is denoted as c.1287 + 1 G>T (or IVS10 + 1 G>T). A subsequent search of the published work in PubMed (www.ncbi.nlm.nih.gov/pubmed/) and ATP2A2 sequence information (University of California Santa Cruz Genome Browser Home [http://genome.ucsc.edu/]) led to the identification of this mutation as novel. The c.1287 + 1 G>T splice site mutation in the ATP2A2 gene destroys the canonical splice donor site in intron 10. It has been predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsensemediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The mechanism of acantholysis in Darier’s disease is still the subject of controversy. Further cataloging of patients’ ATP2A2 gene mutations is required to fully understand the pathological mechanism of this keratinizing disorder.
ACKNOWLEDGMENTS: We thank K. Nakai, T. Moriue and J. Moriue for intellectual discussions. This work was supported by grants from the Ministries of Health, Labor and Welfare, and Education, Culture, Sports, Science and Technology of Japan. CONFLICT OF INTEREST:
None.
Kozo YONEDA,1 Toshio DEMITSU,2 Yasuo KUBOTA1 1 Department of Dermatology, Faculty of Medicine, Kagawa University, Kagawa, and 2Department of Dermatology, Saitama Medical Centre, Jichi Medical University, Saitama, Japan
doi: 10.1111/1346-8138.12437
Correspondence: Kozo Yoneda, M.D., Department of Dermatology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Kitagun Mikicho, Kagawa 761-0793, Japan. Email: [email protected]
© 2014 Japanese Dermatological Association
349
Letters to the Editor
REFERENCES 1 Griffiths WAD, Judge MR, Leigh IM. Darier’s disease. In: Champion RH, Burton JL, Burns PA, Breathnach SM, eds. Textbook of Dermatology, 6th, edn. Vol.2. Oxford: Blackwell Science, 1998; 1546–1549. 2 Bashir R, Munro CS, Mason S et al. Localization of a gene for Darier’s disease. Hum Mol Genet 1993; 2: 19370–19390. 3 Craddock N, Dawson E, Burge S et al. The gene for Darier’s disease maps to chromosome 12q23-q24.1. Hum Mol Genet 1993; 2: 1941– 1943.
4 Sakuntabhai A, Ruiz-Perez V, Carter S et al. Mutations in ATP2A2, encoding a Ca(2 + ) pump, cause Darier disease. Nat Genet 1999; 21: 271–277. 5 Green EK, Gordon-Smith K, Burge SM et al. Novel ATP2A2 mutations in a large sample of individuals with Darier disease. J Dermatol 2013; 40: 259–266.
Novel COL7A1 splice site mutation in severe generalized recessive dystrophic epidermolysis bullosa Dear Editor, A 2-week-old Korean boy presented with bullae and erosions of the entire body since birth (Fig. 1a,b). His feet showed loss of toenails and the toes had gradually fused together after
(a)
6 months. The baby was the first child of healthy, unrelated parents. There was no family history of skin diseases. An indirect immunofluorescence study using anti-type VII collagen monoclonal antibody (Sigma, St Louis, MO, USA)
(b)
(e)
(c)
(d)
(f)
(g)
(h)
Figure 1. (a,b) Severe blisters and erosions on the lower extremities, face and oral mucosa. (c) Immunofluorescence study using anti-type VII collagen antibody revealed the absence of type VII collagen staining at the dermal–epidermal junction in the patient’s skin. (d) Antigen mapping with type VII collagen in the healthy control. (e) Electron microscopy showed separation below the lamina densa and reduced, hypoplastic, anchoring fibrils. Ep, epidermis; D, dermis; asterisk, blister; AF, anchoring fibrils; LD, lamina densa; HD, hemidesmosomes. (f) Direct sequencing analyses revealed a C-to-T transition at nucleotide 3631 in exon 27 of the COL7A1 gene in the proband and his father. (g) A novel splice site mutation at the splice acceptor site of the intron 85/exon 86 junction (IVS 86-2delAG) was detected in the proband and his mother. (h) BspCNI digestion of COL7A1 intron 85 polymerase chain reaction product in restriction fragment length polymorphism (RFLP). In the wild-type allele, the 404-bp fragment was divided into three fragments of 72, 158 and 174 bp by the restriction enzyme BspCNI. The IVS 86-2delAG mutation eliminated the recognition site for BspCNI in one of the mutant alleles, showing a 228 and 174-bp fragment by RFLP.
Correspondence: Soo-Chan Kim, M.D., Ph.D., Department of Dermatology, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonjuro, Gangnam-gu, Seoul 135-720, Korea. Email: [email protected]
350
© 2014 Japanese Dermatological Association
LETTERS TO THE EDITOR
Novel ATP2A2 mutation in a patient with Darier’s disease Dear Editor, Darier’s disease (Online Mendelian Inheritance in Man no. 124200) is a rare, autosomal dominant genodermatosis in which greasy, yellow to brown, crusted papular lesions develop, mainly in the seborrheic areas of the head, neck and trunk.1 The coalescence of papules produces plaques, which may become papillomatous. Darier’s disease usually presents in the second decade, and the course of the disease is characterized by remissions and relapses. Darier’s disease is inherited with a high penetrance, although the phenotypic expression is variable. The genetic defect was mapped to human chromosome 12q23-q24.1 in 1993.2,3 Subsequently, ATA2A2, which encodes the sarco/endoplasmic reticulum Ca2+-ATPase type 2 isoform, a keratinocyte Ca2+ pump, has been identified as the gene responsible.4 To date, more than 187 pathogenic mutations have been described throughout the gene, including missense, nonsense, substitution, insertion and deletion involving both frame-shift and inframe.5 Here, we report a novel c.1287 + 1 G>T (or IVS10 + 1 G>T) mutation in ATA2A2 in a Japanese woman with Darier’s disease. A 38-year-old woman presented with a 5-year history of firm, rather greasy, harsh papules that were skin colored or brown in seborrheic areas of the trunk (Fig. 1a). As the lesions were itchy, she scratched the tops of the papules causing
(a)
(b)
(c)
(d)
Figure 1. (a) Clinical features of seborrheic areas of the trunk. (b) There are many greasy, red to brown, crusted papules. Fine scales are also observed. (c–d) Histological features (hematoxylin–eosin). (c) Lower and (d) higher magnifications of lesions. (c) Mild acanthosis, elongation of rete ridges, and papillomatosis are present. A thick keratotic plug overlies the lesion. Mild mononuclear cell infiltrates around blood vessels in the dermis are also present. (d) Two characteristic types of dyskeratotic cell, corps ronds (white arrows) and corps grains (green arrows), are observed. Scale bar in (c) = 700 lm.
slight hemorrhage (Fig. 1b). There was no family history of the same skin disease. Histological examination revealed focal acantholysis with corps ronds and corps grains (Fig. 1c,d). No nail or oral mucosa changes were observed. Sun exposure and sweating aggravated her condition. After the application of 5% salicylic acid in petroleum, the lesions improved. She has been followed up at regular intervals at our outpatient clinic. Genomic DNA was extracted from peripheral blood leukocytes for genetic testing after obtaining informed consent. Genomic DNA was polymerase chain reaction amplified for the analysis of exons 1–21 of the ATP2A2 gene and their flanking splice sites. A bidirectional sequence was obtained and the DNA sequence was analyzed and compared to the published gene sequence until the mutation was identified. Sequence analysis of the ATP2A2 gene revealed that the patient was heterozygous for the G>T nucleotide substitution at the +1 position of intron 10. This mutation is denoted as c.1287 + 1 G>T (or IVS10 + 1 G>T). A subsequent search of the published work in PubMed (www.ncbi.nlm.nih.gov/pubmed/) and ATP2A2 sequence information (University of California Santa Cruz Genome Browser Home [http://genome.ucsc.edu/]) led to the identification of this mutation as novel. The c.1287 + 1 G>T splice site mutation in the ATP2A2 gene destroys the canonical splice donor site in intron 10. It has been predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsensemediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The mechanism of acantholysis in Darier’s disease is still the subject of controversy. Further cataloging of patients’ ATP2A2 gene mutations is required to fully understand the pathological mechanism of this keratinizing disorder.
ACKNOWLEDGMENTS: We thank K. Nakai, T. Moriue and J. Moriue for intellectual discussions. This work was supported by grants from the Ministries of Health, Labor and Welfare, and Education, Culture, Sports, Science and Technology of Japan. CONFLICT OF INTEREST:
None.
Kozo YONEDA,1 Toshio DEMITSU,2 Yasuo KUBOTA1 1 Department of Dermatology, Faculty of Medicine, Kagawa University, Kagawa, and 2Department of Dermatology, Saitama Medical Centre, Jichi Medical University, Saitama, Japan
doi: 10.1111/1346-8138.12437
Correspondence: Kozo Yoneda, M.D., Department of Dermatology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Kitagun Mikicho, Kagawa 761-0793, Japan. Email: [email protected]
© 2014 Japanese Dermatological Association
349
Letters to the Editor
REFERENCES 1 Griffiths WAD, Judge MR, Leigh IM. Darier’s disease. In: Champion RH, Burton JL, Burns PA, Breathnach SM, eds. Textbook of Dermatology, 6th, edn. Vol.2. Oxford: Blackwell Science, 1998; 1546–1549. 2 Bashir R, Munro CS, Mason S et al. Localization of a gene for Darier’s disease. Hum Mol Genet 1993; 2: 19370–19390. 3 Craddock N, Dawson E, Burge S et al. The gene for Darier’s disease maps to chromosome 12q23-q24.1. Hum Mol Genet 1993; 2: 1941– 1943.
4 Sakuntabhai A, Ruiz-Perez V, Carter S et al. Mutations in ATP2A2, encoding a Ca(2 + ) pump, cause Darier disease. Nat Genet 1999; 21: 271–277. 5 Green EK, Gordon-Smith K, Burge SM et al. Novel ATP2A2 mutations in a large sample of individuals with Darier disease. J Dermatol 2013; 40: 259–266.
Novel COL7A1 splice site mutation in severe generalized recessive dystrophic epidermolysis bullosa Dear Editor, A 2-week-old Korean boy presented with bullae and erosions of the entire body since birth (Fig. 1a,b). His feet showed loss of toenails and the toes had gradually fused together after
(a)
6 months. The baby was the first child of healthy, unrelated parents. There was no family history of skin diseases. An indirect immunofluorescence study using anti-type VII collagen monoclonal antibody (Sigma, St Louis, MO, USA)
(b)
(e)
(c)
(d)
(f)
(g)
(h)
Figure 1. (a,b) Severe blisters and erosions on the lower extremities, face and oral mucosa. (c) Immunofluorescence study using anti-type VII collagen antibody revealed the absence of type VII collagen staining at the dermal–epidermal junction in the patient’s skin. (d) Antigen mapping with type VII collagen in the healthy control. (e) Electron microscopy showed separation below the lamina densa and reduced, hypoplastic, anchoring fibrils. Ep, epidermis; D, dermis; asterisk, blister; AF, anchoring fibrils; LD, lamina densa; HD, hemidesmosomes. (f) Direct sequencing analyses revealed a C-to-T transition at nucleotide 3631 in exon 27 of the COL7A1 gene in the proband and his father. (g) A novel splice site mutation at the splice acceptor site of the intron 85/exon 86 junction (IVS 86-2delAG) was detected in the proband and his mother. (h) BspCNI digestion of COL7A1 intron 85 polymerase chain reaction product in restriction fragment length polymorphism (RFLP). In the wild-type allele, the 404-bp fragment was divided into three fragments of 72, 158 and 174 bp by the restriction enzyme BspCNI. The IVS 86-2delAG mutation eliminated the recognition site for BspCNI in one of the mutant alleles, showing a 228 and 174-bp fragment by RFLP.
Correspondence: Soo-Chan Kim, M.D., Ph.D., Department of Dermatology, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonjuro, Gangnam-gu, Seoul 135-720, Korea. Email: [email protected]
350
© 2014 Japanese Dermatological Association
