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: 6.37). 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, 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.
    The EMBO Journal 04/2012; 31(10):2261-74. DOI:10.1038/emboj.2012.79 · 10.75 Impact Factor
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    • "Another intriguing discovery of our study is the brain specificity of the splicing defect caused by the c.548G>T mutation, sparing other tissues from detrimental effects associated with reduced PSEN1 expression. Recent studies have shown an association between haploinsufficiency of γ-secretase component proteins and familial acne inversa (Kelleher and Shen, 2010; Wang et al., 2010; Li et al., 2011; Pink et al., 2011). However, our molecular analysis of c.548G>T KI mice showed that levels of Psen1 mRNAs are only reduced in the brain (Figure 4). "
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    ABSTRACT: Mutations in the presenilin-1 (PSEN1) gene are associated with familial Alzheimer's disease and frontotemporal dementia (FTD). Interestingly, neuropathological analysis of a Belgian FTD family carrying a PSEN1 c.548G>T mutation confirmed neurodegeneration in the absence of amyloid plaques. To investigate the impact of the c.548G>T mutation on presenilin-1 (PS1) function in vivo, we introduced this mutation into the genomic Psen1 locus. The resulting c.548G>T knock-in (KI) mice are viable but express markedly lower levels of Psen1 mRNA and protein in the brain. This reduction is due to production of aberrantly spliced transcripts lacking either exon 6 or exons 6 and 7 and their subsequent degradation via non-sense-mediated decay (NMD); inhibition of NMD by cycloheximide treatment stabilized these transcripts and restored the level of Psen1 mRNA in KI/KI brains. Interestingly, the reduction of Psen1 mRNA expression and the degradation of aberrant Psen1 splice products occur exclusively in the brain but not in other tissues. Consistent with decreased Psen1 expression, γ-secretase activity was strongly reduced in the cerebral cortex of KI mice, as measured by de novo γ-secretase-mediated cleavage of APP and Notch. Moreover, PS1 expressed from Psen1 cDNA carrying the c.548G>T mutation displayed normal γ-secretase activity in cultured cells, indicating that the corresponding p.183G>V amino acid substitution does not affect γ-secretase activity. Finally, Psen1 c.548G>T(KI/KI);Psen2(-/-) mice exhibited mild spatial memory deficits in the Morris water maze task. Together, our findings demonstrate that the c.548G>T mutation results in a brain-specific loss of presenilin function due to decreased Psen1 mRNA expression.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 04/2012; 32(15):5085-96. DOI:10.1523/JNEUROSCI.0317-12.2012 · 6.75 Impact Factor
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    ABSTRACT: Schätzungsweise 1% der Bevölkerung leidet an Hidradenitis suppurativa/Acne inversa, einer chronisch entzündlichen Erkrankung, die Patienten und Ärzte vor große Herausforderungen stellt. Die progrediente Erkrankung isoliert die Patienten zunehmend sozial und bereitet konstante Schmerzen. Oftmals vergehen Jahre bis zur korrekten Diagnosestellung. Die behandelnden Hautärzte werden mit einem rezidivierenden Krankheitsbild und oftmals frustrierten Patienten konfrontiert. Der Beitrag vermittelt Basiswissen und ordnet Therapiemöglichkeiten.
    Der Hautarzt 04/2013; 64(1). DOI:10.1007/s00105-012-2479-8 · 0.54 Impact Factor
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