Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease

Abstract

Darier disease (DD) is an autosomal-dominant skin disorder characterized by loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization. Recently we constructed a 2.4-Mb, P1-derived artificial chromosome contig spanning the DD candidate region on chromosome 12q23-24.1. After screening several genes that mapped to this region, we identified mutations in the ATP2A2 gene, which encodes the sarco/endoplasmic reticulum Ca2(+)-ATPase type 2 isoform (SERCA2) and is highly expressed in keratinocytes. Thirteen mutations were identified, including frameshift deletions, in-frame deletions or insertions, splice-site mutations and non-conservative missense mutations in functional domains. Our results demonstrate that mutations in ATP2A2 cause DD and disclose a role for this pump in a Ca(2+)-signalling pathway regulating cell-to-cell adhesion and differentiation of the epidermis.

Genetic or epigenetic difference causing discordance between monozygotic twins as a clue to molecular basis of mental disorders

“…Darier's disease is an autosomal dominantly inherited dermatological disease caused by mutations in the ATP2A2, encoding endoplasmic reticulum Ca 2 þ -ATPase. 20 In this pair of MZ twins discordant for Darier's disease, a point mutation of ATP2A2 was identified. This mutation, G23E, was not found in the healthy co-twin and their parents, suggesting that it was a de novo mutation.…”

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

“…84,146 However, CDPX2 may present with severe CIE or collodion membrane and is therefore regarded as an ichthyosis (Fig 4, F ). 147 Darier disease 148,149 and HaileyeHailey disease 150 are autosomal dominant genodermatoses 151,152 The typical lesions of Darier diseaseeusually beginning in adolescenceeare tiny keratotic papules with a firmly adherent keratin cap, and are most often found on the seborrheic areas, scalp, and extremities; generalized involvement is very rare.…”

Defective channels lead to an impaired skin barrier

“…In addition, the importance of normal Ca 2+ homeostasis for the maintenance of the epidermal barrier is highlighted in patients with Darier's disease. In Darier's disease, skin fragility and hyperkeratosis are associated with mutations in the ATP2A2 gene encoding SERCA2, a transmembrane ATPase pump that mediates the uptake of cytosolic Ca 2+ into internal ER Ca 2+ stores (Sakuntabhai et al, 1999). Both mouse and human keratinocytes with reduced levels of SERCA2 show upregulation of TRPC1 and increased Ca 2+ entry (Pani et al, 2006).…”