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6.
Br J Dermatol ; 178(2): 502-508, 2018 02.
Article in English | MEDLINE | ID: mdl-28922471

ABSTRACT

BACKGROUND: Dowling-Degos disease (DDD), featuring reticulate pigmentation, and familial hidradenitis suppurativa (HS) share many clinical features including autosomal dominant inheritance, flexural location and follicular defects. The coexistence of the two disorders was recently found to result from mutations in PSENEN, encoding the γ-secretase subunit protein presenilin enhancer. OBJECTIVES: To investigate PSENEN mutations in a series of four unrelated patients who presented with combined DDD and HS. METHODS: Mutation and haplotype analysis of PSENEN by polymerase chain reaction, and cellular assays investigating the Notch signalling pathway. RESULTS: Here we report four families of Jewish Ashkenazi origin who presented with clinical features characteristic of both disorders. All patients were found to carry the same, heterozygous mutation in PSENEN (c.168T>G, p.Y56X). Haplotype analysis revealed that the mutation originated from a common ancestor. Genes associated with DDD, as well as HS, have been shown to encode important regulators of Notch signalling. Accordingly, using a reporter assay, we demonstrated decreased Notch activity in a patient's keratinocytes. CONCLUSIONS: The present data confirm the genetic basis of the combined DDD-HS phenotype and suggest that Notch signalling may play a central role in the pathogenesis of this rare condition.


Subject(s)
Amyloid Precursor Protein Secretases/genetics , Founder Effect , Hidradenitis Suppurativa/genetics , Hyperpigmentation/genetics , Membrane Proteins/genetics , Mutation/genetics , Skin Diseases, Genetic/genetics , Skin Diseases, Papulosquamous/genetics , Adult , Female , Humans , Male , Phenotype , Receptors, Notch/genetics , Signal Transduction/genetics , Young Adult
7.
Clin Exp Dermatol ; 43(2): 187-190, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29277919

ABSTRACT

Epidermolytic ichthyosis (EI) is a rare skin disorder caused by mutations in the genes KRT1 and KRT10, and is usually inherited in an autosomal dominant fashion. Only five recessive mutations causing EI have been described, all of which are located in the central region of the KRT10 gene. In the current study, we aimed to identify the genetic defect underlying EI in a 12-year-old patient. Direct sequencing of the patient's genomic DNA revealed a novel homozygous nonsense mutation residing within the proximal part KRT10 first exon. The mutation was found to co-segregate with the disease phenotype in an autosomal recessive fashion. Using real-time quantitative PCR, we found an almost two-fold decrease in KRT10 expression in the patient's skin compared with the skin of healthy controls. Western blot analysis showed complete absence of keratin 10 protein in the patient's skin, suggesting early protein degradation.


Subject(s)
Codon, Nonsense , Hyperkeratosis, Epidermolytic/genetics , Keratin-10/genetics , Biopsy , Child , DNA Mutational Analysis , Female , Humans , Hyperkeratosis, Epidermolytic/metabolism , Hyperkeratosis, Epidermolytic/pathology , Keratin-10/metabolism , Skin/metabolism , Skin/pathology
8.
Clin Exp Dermatol ; 41(8): 915-918, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27730671

ABSTRACT

Epidermolysis bullosa simplex (EBS) is the most common form of EB. Eight different genes have been implicated in the pathogenesis of different types of EBS, but a substantial portion of the cases cannot be attributed to mutations in known genes. Recently, recessive mutations in the gene EXPH5 (encoding exophilin-5, also known as Slac2-b) were identified in patients affected with a mild form of EBS. We used immunohistochemistry, Sanger sequencing and PCR-restriction fragment length polymorphism analysis to identify the cause of mild congenital skin fragility in a 3-year-old girl. No mutations were detected in KRT5 or KRT14, but we identified a novel homozygous deletion in EXPH5, which was found to cosegregate with the disease phenotype in the family. Our results further expand the spectrum of mutations in EXPH5. Appraisal of the present case against previously reported patients indicate that EXPH5 mutations result in a distinctive skin fragility phenotype, with minimal blistering compared with other forms of basal EBS.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Epidermolysis Bullosa Simplex/genetics , Sequence Deletion , Child, Preschool , Female , Humans
10.
Gene Ther ; 22(7): 521-7, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25762284

ABSTRACT

The integrase (Int) encoded by the lambdoid coliphage HK022 targets in its host chromosome a 21 base pair (bp) recombination site termed attB or BOB'. attB comprises two 7 bp partially inverted (palindromic) Int-binding sites of 7 bp each termed B and B'. B and B' flank a central 7 bp crossover site or 'overlap' (O). We show that replacing O with a random 7 bp sequence supports Int-mediated site-specific recombination as long as the cognate and larger phage recombination site attP features an identical O sequence. This promiscuity allowed us to identify on the human genome several native active secondary attB sites ('attB') with random overlaps that flank human deleterious mutations, raising the prospect of using such sites to cure the 'attB'-flanked mutations by Int-catalyzed RMCE (recombinase-mediated cassette exchange) reactions. An analysis of such active and inactive 'attB's suggested a minimal 14-15 bp attB consensus sequence (instead of the 21 bp) with a reduced 3 bp palindrome.


Subject(s)
Coliphages/metabolism , Genetic Therapy , Genome, Human , Integrases/metabolism , Recombination, Genetic , Attachment Sites, Microbiological , Coliphages/genetics , Escherichia coli K12 , HEK293 Cells , Humans , Integrases/genetics , Mutation
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