Article

PSENEN and NCSTN mutations in familial hidradenitis suppurativa (Acne Inversa).

Department of Medical and Molecular Genetics, King's College London School of Medicine, London, UK.
Journal of Investigative Dermatology (Impact Factor: 7.22). 03/2011; 131(7):1568-70. DOI: 10.1038/jid.2011.42
Source: PubMed

ABSTRACT

HS, hidradenitis suppurativa

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Available from: Glen Brice, Jul 28, 2014
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    • "However, in British and Indian families with autosomal dominant inheritance of HS no mutations in NCSTN and PSENEN or linkage to 1p21.1–1q25.3, respectively, were found and most cases of HS do not follow simple Mendelian inheritance[18,19]. The present study is the first, to our knowl-edge, to investigate the genetic background of HS in such a large number of patients that are not relatives. "
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    ABSTRACT: Antigen presentation in chronic skin disorders is mediated through the interleukin (IL)-12/IL-23 pathway and, hence, through the IL-12 receptor. Recent evidence suggesting dysregulated antigen presentation in skin lesions of hidradenitis suppurativa (HS) led to investigate the role of single nucleotide polymorphisms (SNPs) of the gene IL-12RB1 coding for the IL12-Rβ1 receptor subunit. Genomic DNA was isolated from 139 patients and 113 healthy controls; nine SNPs in the transcribed region of IL12RB1 were genotyped. No significant differences of genotype and allele frequencies were found between the two groups. Two common haplotypes were recognized, namely h1 and h2. Carriage of h2 related with minor frequency alleles was associated with a greater risk for the acquisition of Hurley III disease stage and with the involvement of a greater number of skin areas. Patients with the h1 haplotype presented disease at an older age. This is the genetic study enrolling the largest number of patients with HS to date. Although SNPs of IL12RB1 do not seem to convey genetic predisposition, they are associated directly with the phenotype of the disease.
    Full-text · Article · Apr 2013 · Cytokine
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    • "However, when haploinsufficiency of γ-secretase components was identified in human kindred suffering from the inflammatory skin disease hidradenitis suppurativa (HS) [11], [12], [13], there was no indication of cognitive deficits in these patients. γ-secretase mutations were seen in three of the four proteins: Nicastrin (Nct), Pen-2, and PS, which are all required for efficient proteolytic activity. "
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    ABSTRACT: Previous studies suggest that loss of γ-secretase activity in postnatal mouse brains causes age-dependent memory impairment and neurodegeneration. Due to the diverse array of γ-secretase substrates, it remains to be demonstrated whether loss of cleavage of any specific substrate(s) is responsible for these defects. The bulk of the phenotypes observed in mammals deficient for γ-secretase or exposed to γ-secretase inhibitors are caused by the loss of Notch receptor proteolysis. Accordingly, inhibition of Notch signaling is the main cause for untoward effects for γ-secretase inhibitors as therapeutics for Alzheimer's disease. Therefore, we wished to determine if loss of canonical Notch signaling is responsible for the age-dependent neurodegeneration observed upon γ-secrectase deficiency in the mouse brain. We generated postnatal forebrain-specific RBPj conditional knockout (cKO) mice using the CamKII-Cre driver and examined behavior and brain pathology in 12-18 month old animals. Since all four mammalian Notch receptor homologues signal via this DNA binding protein, these mice lack canonical Notch signaling. We found that loss of RBPj in mature excitatory neurons was well tolerated, with no evidence for neurodegeneration or of learning and memory impairment in mice aged up to 18 months. The only phenotypic deficit we observed in the RBPj-deficient mice was a subtle abnormality in olfactory preferences, particularly in females. We conclude that the loss of canonical Notch signaling through the four receptors is not responsible for age-dependent neurodegeneration or learning and memory deficits seen in γ-secretase deficient mice.
    Full-text · Article · Oct 2012 · PLoS ONE
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    • "However, this last argument has been considerably weakened by follow-up studies showing that neurodegeneration was likely caused by a second mutation in the progranulin gene in one case (Boeve et al, 2006), whereas in a second case abundant amyloid deposition in the frontal lobe appeared at autopsy (for further discussion, see Bergmans and De Strooper, 2010). On the other hand, recent observations in patients suffering from familial acne inversa in China (Wang et al, 2010) and independently in Great Britain (Pink et al, 2011) raise doubts about the validity of the 'simple' g-secretase loss-of-function hypothesis. This condition appears to be associated with the haploinsufficiency of g-secretase subunit genes (Nicastrin, Pen2) and most likely involves a deficiency in Notch cell signalling. "
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    ABSTRACT: The mechanisms by which mutations in the presenilins (PSEN) or the amyloid precursor protein (APP) genes cause familial Alzheimer disease (FAD) are controversial. FAD mutations increase the release of amyloid β (Aβ)42 relative to Aβ40 by an unknown, possibly gain-of-toxic-function, mechanism. However, many PSEN mutations paradoxically impair γ-secretase and 'loss-of-function' mechanisms have also been postulated. Here, we use kinetic studies to demonstrate that FAD mutations affect Aβ generation via three different mechanisms, resulting in qualitative changes in the Aβ profiles, which are not limited to Aβ42. Loss of ɛ-cleavage function is not generally observed among FAD mutants. On the other hand, γ-secretase inhibitors used in the clinic appear to block the initial ɛ-cleavage step, but unexpectedly affect more selectively Notch than APP processing, while modulators act as activators of the carboxypeptidase-like (γ) activity. Overall, we provide a coherent explanation for the effect of different FAD mutations, demonstrating the importance of qualitative rather than quantitative changes in the Aβ products, and suggest fundamental improvements for current drug development efforts.
    Full-text · Article · Apr 2012 · The EMBO Journal
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