Molecular genetic support for the rule of dichotomy in type 2 segmental Darier disease

Fölster‐Holst, Regina; Nellen, Ruud G. L.; Jensen, Jens‐Michael; Poblete‐Gutiérrez, Pamela; Steijlen, P.M.; Schwarz, Thomas; Happle, Rudolf; Geel, Michel van; Frank, Jorge

doi:10.1111/j.1365-2133.2011.10593.x

Cited by 37 publications

(31 citation statements)

References 12 publications

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“…1 In type 2 mosaicism, a heterozygous embryo harbours a germline mutation for an autosomal dominant skin disease, and a segmental area of the skin that is far more severely affected as a result of loss of heterozygosity for the underlying mutation, giving rise to either homozygosity or hemizygosity. 3,4 Here we report a patient with congenital, pronounced, unilateral lesions of Gorlin syndrome (naevoid basal cell carcinoma syndrome, OMIM 109400), and we present, for the first time, molecular data providing evidence of a type 2 segmental manifestation of this autosomal dominant disorder. 2 To date, however, molecular proof of the concept has been provided in only a few skin disorders.…”

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“…2 To date, however, molecular proof of the concept has been provided in only a few skin disorders. 3,4 Here we report a patient with congenital, pronounced, unilateral lesions of Gorlin syndrome (naevoid basal cell carcinoma syndrome, OMIM 109400), and we present, for the first time, molecular data providing evidence of a type 2 segmental manifestation of this autosomal dominant disorder.…”

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Molecular evidence of type 2 mosaicism in Gorlin syndrome

et al. 2013

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Summary We present a 12‐year‐old girl with a family history of Gorlin syndrome who had unilateral, segmentally arranged basaloid skin tumours present since birth, ipsilateral, palmoplantar pits of rather large size distributed along Blaschko lines, and an ipsilateral odontogenic keratocyst. The patient and her father were heterozygous for a germline mutation in the form of a single‐base substitution in exon 18 of the PTCH1 gene. In the patient's lesional skin, a microdeletion in exon 3 of PTCH1 was detected, giving rise to a truncated protein. This additional mutation was ruled out in the contralateral skin and in blood lymphocytes, thus confirming its mosaic state. In this way we provide for the first time molecular proof of a type 2 segmental involvement of this autosomal dominant trait.

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Molecular evidence of type 2 mosaicism in Gorlin syndrome

et al. 2013

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“…AKV is considered to be allelic to DD, since ATP2A2 mutations have been found in patients with AKV [Dhitavat et al, 2003b]. DD and HHD may occur in a segmental distribution, either due to a postzygotic somatic mutation (type I segmental disease) [Sakuntabhai et al, 2000] or postzygotic loss of heterozygosity for the wild-type allele in a patient heterozygous for a germline ATP2A2 mutation (type II segmental disease) [Fölster-Holst et al, 2012].…”

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confidence: 99%

Mendelian Disorders of Cornification Caused by Defects in Intracellular Calcium Pumps: Mutation Update and Database for Variants in ATP2A2 and ATP2C1 Associated with Darier Disease and Hailey-Hailey Disease

et al. 2017

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The two disorders of cornification associated with mutations in genes coding for intracellular calcium pumps are Darier disease (DD) and Hailey-Hailey disease (HHD). DD is caused by mutations in the ATP2A2 gene, whereas the ATP2C1 gene is associated with HHD. Both are inherited as autosomal-dominant traits. DD is mainly defined by warty papules in seborrheic and flexural areas, whereas the major symptoms of HHD are vesicles and erosions in flexural skin. Both phenotypes are highly variable. In 12%-40% of DD patients and 12%-55% of HHD patients, no mutations in ATP2A2 or ATP2C1 are found. We provide a comprehensive review of clinical variability in DD and HHD and a review of all reported mutations in ATP2A2 and ATP2C1. Having the entire spectrum of ATP2A2 and ATP2C1 variants allows us to address the question of a genotype-phenotype correlation, which has not been settled unequivocally in DD and HHD. We created a database for all mutations in ATP2A2 and ATP2C1 using the Leiden Open Variation Database (LOVD v3.0), for variants reported in the literature and future inclusions. This data may be of use as a reference tool in further research on treatment of DD and HHD.

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“…To date more than 187 pathogenic mutations have been described throughout the gene, including missense, nonsense, substitutions, insertions and deletions both frame‐shift and in‐frame (Miyauchi et al., for all references 2006 and earlier, and subsequent references). These mutations do not seem to cluster within “hot‐spot” regions throughout the primary sequence of the SERCA2b molecule and most are unique within individual families.…”

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Novel ATP2A2 mutations in a large sample of individuals with Darier disease

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Gordon‐Smith

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et al. 2013

The Journal of Dermatology

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Darier disease (DD) is a rare autosomal dominantly inherited skin disorder caused by mutations in ATP2A2, which is expressed in both the skin and the brain and encodes for SERCA2. We have screened the coding regions of ATP2A2 in a total of 95 unrelated individuals with DD to identify the pathogenic mutations. We identified 66 potentially pathogenic mutations in ATP2A2 for 74 of the 95 individuals with DD of which 45 (68%) are thought to be novel. Forty-nine (74%) are unique to an individual and 17 (26%) were found in more than one individual or overlap with previously identified variants. The results suggest that mutations in ATP2A2 may not be as family-specific as first thought. The spectrum of mutations identified will inform understanding of the pathogenesis of DD.

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Molecular genetic support for the rule of dichotomy in type 2 segmental Darier disease

Cited by 37 publications

References 12 publications

Molecular evidence of type 2 mosaicism in Gorlin syndrome

Molecular evidence of type 2 mosaicism in Gorlin syndrome

Mendelian Disorders of Cornification Caused by Defects in Intracellular Calcium Pumps: Mutation Update and Database for Variants in ATP2A2 and ATP2C1 Associated with Darier Disease and Hailey-Hailey Disease

Novel ATP2A2 mutations in a large sample of individuals with Darier disease

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