Acta Dermato-Venereologica 99-1CompleteContent | Page 33
SHORT COMMUNICATION
115
A Postzygotic ATP2A2 Novel Mutation Identified by Next-generation Sequencing in Mosaic Darier
Disease
Liliana GUERRA 1 , Cristina PEDICELLI 2 , Vittoria PROTO 1 , Angelo Giuseppe CONDORELLI 3 , Cinzia MAZZANTI 2 and Daniele
CASTIGLIA 1
1
Laboratory of Molecular and Cell Biology, 2 1 st Dermatology Division, Istituto Dermopatico dell’Immacolata, IDI-IRCCS, and 3 Genetic and
Rare Diseases Research Area, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy. E-mail: [email protected]
Accepted Aug 7, 2018; Epub ahead of print Aug 7, 2018
whereas a loss-of heterozygosity (LOH) in a heterozygous
Darier disease (DD) is a rare skin condition with autoso-
mal dominant inheritance that manifests in childhood or
individual was hypothesized for segmental DD type 2 (10).
adolescence (1, 2). It is characterized by keratotic papules
Although there is no direct evidence for LOH as a causal
that may coalesce into large warty plaques, predominantly
event for DD type 2, molecular genetic support has been
affecting seborrhoeic areas, such as the forehead, central
provided (8). We report here on the molecular basis of the
chest, back and scalp borders, usually accompanied by
mosaicism in an Italian woman with segmental DD type 1.
palmoplantar pits and characteristic nail changes (i.e.
longitudinal leukonychia and V-shaped notches at the
CASE REPORT
distal end of the nail plate) (1, 3). Involvement of in-
tertriginous areas and psychiatric symptoms may also
A 47-year-old woman presented with keratotic papules on the right
side of her trunk, and right arm and leg. The lesions appeared on
be present (1, 3). Heat or humidity, excessive sweating,
exposure to ultraviolet (UV) light, friction,
medications and infections, as well as preg-
nancy or delivery, aggravate the disorder (3).
Histologically, DD is characterized by loss
of adhesion between epidermal cells, termed
acantholysis, leading to suprabasal cleavage
and abnormal keratinization, which manifests
as corps ronds and grains (4).
DD is caused by mutations in the ATP2A2
gene, which encodes isoforms of the sarco/en-
doplasmic reticulum ATPase type 2 (SERCA2)
in keratinocytes and cells from other tissues
(5). SERCA2 is a calcium pump incorporated
in the endoplasmic reticulum (ER) membrane
that regulates Ca 2+ transport from the cyto-
plasm into the ER lumen. It is organized in 10
transmembrane helices (M1–M10) intercalated
by 5 stalk sectors (S1–S5), and in a cytosol-
exposed region comprising the phosphoryla-
tion and ATP-binding domains (5). In 2000,
genetic mosaicism for mutations in ATP2A2
was demonstrated to cause the segmental
form of the disease (6), which is quite rare.
Segmental DD can manifest in a mosaic pattern
distinctive of 2 disease subtypes: segmental
DD type 1, which is characterized by warty
papules distributed in a linear pattern on a
background of clinically normal skin, and seg-
mental DD type 2, in which linear DD lesions
Fig. 1. Clinical and histopathological findings. (a, b) Hyperkeratotic papules following
the Blaschko’s lines over the right side of the patient’s trunk and her right arm. (a) Note
are usually more severe and may manifest early
the sharp midline demarcation on the abdomen, clearly visible after sun exposure during
after birth, superimposed on a background of
the summer, on a background of post-inflammatory hypopigmentation. (c) Hyperkeratotic
generalized DD (7, 8). Segmental DD type
papules on the right leg during the winter. (d) Hyperkeratosis with parakeratosis, acanthosis
1 was hypothesized to result from a de novo
and suprabasal acantholysis in the haematoxylin-eosin staining. Higher magnification
shows dyskeratotic cells with a pyknotic nucleus surrounded by a halo, termed corps
postzygotic ATP2A2 mutation that occurs
ronds, within the spinous layer (d: blue inset, yellow circles), and flattened dyskeratotic
during embryogenesis, and a few studies have
cells with an elongated nucleus, termed grains, within the parakeratotic horny layer (d:
provided genetic proof for this aetiology (4, 9),
black inset, green circle). Haematoxylin-eosin staining (d) × 200 (left panel).
This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta
Journal Compilation © 2019 Acta Dermato-Venereologica.
doi: 10.2340/00015555-3018
Acta Derm Venereol 2019; 99: 115–116