ATP2A2 mutations in Darier's disease: Variant cutaneous phenotypes are associated with missense mutations, but neuropsychiatric features are independent of mutation class

Victor L. Ruiz-Perez, Simon A. Carter, Eugene Healy, Carole Todd, Jonathan L. Rees, Peter M. Steijlen, Andrew J. Carmichael, Helen M. Lewis, D. Hohl, Peter Itin, Anders Vahlquist, T. Gobello, C. Mazzanti, R. Reggazini, Gyula Nagy, Colin S. Munro, Tom Strachan

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Abstract

Darier's disease (DD) is an autosomal dominant skin disorder characterized clinically by multiple keratotic papules, and histologically by focal loss of adhesion between epidermal cells (acantholysis) and by abnormal keratinization. Variant forms of cutaneous phenotype, sometimes familial, have been described. Associated neuropsychiatric features, including mental handicap, schizophrenia, bipolar disorder and epilepsy, have also been reported. The cause of DD was shown recently to be mutation in the ATP2A2 gene at 12q24.1, which encodes the sarco-endoplasmic reticulum calcium ATPase type 2 (SERCA2). Here, we show that while both common isoforms of SERCA2 are expressed in the cytoplasm of cultured keratinocytes and fibroblasts, in adult skin sections only the longer isoform, SERCA2b, was expressed abundantly in epidermal structures. Extended mutation analysis in European DD patients using single-strand conformation polymorphism and/or direct sequencing identified 40 different patient-specific mutations in 47 families. The majority (23/40) were likely to result in nonsense-mediated RNA decay. The remaining 17 were missense mutations distributed throughout the protein and were associated significantly with atypical clinical features. The clearest association was with the familial haemorrhagic variant where all four families tested had a missense mutation. Three of the families (one Scottish family and two unrelated Italian families) exhibited the same N767S substitution in the M5 transmembrane domain, and a fourth family, from Sweden, had a C268F substitution in the M3 transmembrane domain. Neuropsychiatric features did not appear to be associated with a specific class of mutation and may be an intrinsic, but inconsistent, effect of defective ATP2A2 expression.

Original languageEnglish
Pages (from-to)1621-1630
Number of pages10
JournalHuman Molecular Genetics
Volume8
Issue number9
DOIs
Publication statusPublished - 1999

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Darier Disease
Missense Mutation
Phenotype
Skin
Mutation
Calcium-Transporting ATPases
Endoplasmic Reticulum
Protein Isoforms
Acantholysis
Focal Adhesions
RNA Stability
Bipolar Disorder
Keratinocytes
Sweden
Epilepsy
Schizophrenia
Cytoplasm
Fibroblasts
Genes

ASJC Scopus subject areas

  • Genetics

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ATP2A2 mutations in Darier's disease : Variant cutaneous phenotypes are associated with missense mutations, but neuropsychiatric features are independent of mutation class. / Ruiz-Perez, Victor L.; Carter, Simon A.; Healy, Eugene; Todd, Carole; Rees, Jonathan L.; Steijlen, Peter M.; Carmichael, Andrew J.; Lewis, Helen M.; Hohl, D.; Itin, Peter; Vahlquist, Anders; Gobello, T.; Mazzanti, C.; Reggazini, R.; Nagy, Gyula; Munro, Colin S.; Strachan, Tom.

In: Human Molecular Genetics, Vol. 8, No. 9, 1999, p. 1621-1630.

Research output: Contribution to journalArticle

Ruiz-Perez, VL, Carter, SA, Healy, E, Todd, C, Rees, JL, Steijlen, PM, Carmichael, AJ, Lewis, HM, Hohl, D, Itin, P, Vahlquist, A, Gobello, T, Mazzanti, C, Reggazini, R, Nagy, G, Munro, CS & Strachan, T 1999, 'ATP2A2 mutations in Darier's disease: Variant cutaneous phenotypes are associated with missense mutations, but neuropsychiatric features are independent of mutation class', Human Molecular Genetics, vol. 8, no. 9, pp. 1621-1630. https://doi.org/10.1093/hmg/8.9.1621
Ruiz-Perez, Victor L. ; Carter, Simon A. ; Healy, Eugene ; Todd, Carole ; Rees, Jonathan L. ; Steijlen, Peter M. ; Carmichael, Andrew J. ; Lewis, Helen M. ; Hohl, D. ; Itin, Peter ; Vahlquist, Anders ; Gobello, T. ; Mazzanti, C. ; Reggazini, R. ; Nagy, Gyula ; Munro, Colin S. ; Strachan, Tom. / ATP2A2 mutations in Darier's disease : Variant cutaneous phenotypes are associated with missense mutations, but neuropsychiatric features are independent of mutation class. In: Human Molecular Genetics. 1999 ; Vol. 8, No. 9. pp. 1621-1630.
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abstract = "Darier's disease (DD) is an autosomal dominant skin disorder characterized clinically by multiple keratotic papules, and histologically by focal loss of adhesion between epidermal cells (acantholysis) and by abnormal keratinization. Variant forms of cutaneous phenotype, sometimes familial, have been described. Associated neuropsychiatric features, including mental handicap, schizophrenia, bipolar disorder and epilepsy, have also been reported. The cause of DD was shown recently to be mutation in the ATP2A2 gene at 12q24.1, which encodes the sarco-endoplasmic reticulum calcium ATPase type 2 (SERCA2). Here, we show that while both common isoforms of SERCA2 are expressed in the cytoplasm of cultured keratinocytes and fibroblasts, in adult skin sections only the longer isoform, SERCA2b, was expressed abundantly in epidermal structures. Extended mutation analysis in European DD patients using single-strand conformation polymorphism and/or direct sequencing identified 40 different patient-specific mutations in 47 families. The majority (23/40) were likely to result in nonsense-mediated RNA decay. The remaining 17 were missense mutations distributed throughout the protein and were associated significantly with atypical clinical features. The clearest association was with the familial haemorrhagic variant where all four families tested had a missense mutation. Three of the families (one Scottish family and two unrelated Italian families) exhibited the same N767S substitution in the M5 transmembrane domain, and a fourth family, from Sweden, had a C268F substitution in the M3 transmembrane domain. Neuropsychiatric features did not appear to be associated with a specific class of mutation and may be an intrinsic, but inconsistent, effect of defective ATP2A2 expression.",
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T2 - Variant cutaneous phenotypes are associated with missense mutations, but neuropsychiatric features are independent of mutation class

AU - Ruiz-Perez, Victor L.

AU - Carter, Simon A.

AU - Healy, Eugene

AU - Todd, Carole

AU - Rees, Jonathan L.

AU - Steijlen, Peter M.

AU - Carmichael, Andrew J.

AU - Lewis, Helen M.

AU - Hohl, D.

AU - Itin, Peter

AU - Vahlquist, Anders

AU - Gobello, T.

AU - Mazzanti, C.

AU - Reggazini, R.

AU - Nagy, Gyula

AU - Munro, Colin S.

AU - Strachan, Tom

PY - 1999

Y1 - 1999

N2 - Darier's disease (DD) is an autosomal dominant skin disorder characterized clinically by multiple keratotic papules, and histologically by focal loss of adhesion between epidermal cells (acantholysis) and by abnormal keratinization. Variant forms of cutaneous phenotype, sometimes familial, have been described. Associated neuropsychiatric features, including mental handicap, schizophrenia, bipolar disorder and epilepsy, have also been reported. The cause of DD was shown recently to be mutation in the ATP2A2 gene at 12q24.1, which encodes the sarco-endoplasmic reticulum calcium ATPase type 2 (SERCA2). Here, we show that while both common isoforms of SERCA2 are expressed in the cytoplasm of cultured keratinocytes and fibroblasts, in adult skin sections only the longer isoform, SERCA2b, was expressed abundantly in epidermal structures. Extended mutation analysis in European DD patients using single-strand conformation polymorphism and/or direct sequencing identified 40 different patient-specific mutations in 47 families. The majority (23/40) were likely to result in nonsense-mediated RNA decay. The remaining 17 were missense mutations distributed throughout the protein and were associated significantly with atypical clinical features. The clearest association was with the familial haemorrhagic variant where all four families tested had a missense mutation. Three of the families (one Scottish family and two unrelated Italian families) exhibited the same N767S substitution in the M5 transmembrane domain, and a fourth family, from Sweden, had a C268F substitution in the M3 transmembrane domain. Neuropsychiatric features did not appear to be associated with a specific class of mutation and may be an intrinsic, but inconsistent, effect of defective ATP2A2 expression.

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