Two novel mutations of the nicastrin gene in Chinese patients with acne inversa

Li, C.‐R.; Jiang, Miao; Shen, Dan-Bei; Xu, Haoxiang; Wang, H.‐S.; Yao, Xu; Zhang, Y.; Zhou, Wu-qing; Wang, B.

doi:10.1111/j.1365-2133.2011.10372.x

Cited by 57 publications

(56 citation statements)

References 14 publications

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“…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).…”

Section: Discussionmentioning

confidence: 99%

Familial Frontotemporal Dementia-AssociatedPresenilin-1 c.548G>TMutation Causes Decreased mRNA Expression and Reduced Presenilin Function in Knock-In Mice

Watanabe¹,

Xia²,

Kanekiyo³

et al. 2012

J. Neurosci.

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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 knockin (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 nonsense-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.

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Section: Discussionmentioning

confidence: 99%

Familial Frontotemporal Dementia-AssociatedPresenilin-1 c.548G>TMutation Causes Decreased mRNA Expression and Reduced Presenilin Function in Knock-In Mice

Watanabe¹,

Xia²,

Kanekiyo³

et al. 2012

J. Neurosci.

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“…This unique role may be caused by γ-secretase-independent activities of PS that are more relevant to AD pathogenesis, by a higher intrinsic mutation rate of the human PSEN genes than of the other γ-secretase subunit genes, or by PS forming the catalytic core of the γ-secretase complex. Interestingly, recent human genetic studies identified large numbers of loss-of-function mutations in the Nct (17) and Pen-2 (3) genes that are associated with familial acne inversa or hidradenitis suppurativa (27)(28)(29)(30)(31). The lack of mutations identified in the Aph-1A and Aph-1B genes may reflect the genetic redundancy of the Aph-1 family; however, one mutation was reported in the PSEN1 gene despite the presence of its family member PSEN2 (27).…”

Section: Discussionmentioning

confidence: 99%

Synaptic function of nicastrin in hippocampal neurons

Lee

Sharma

Südhof

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Synaptic dysfunction is widely thought to play a key role in the pathogenesis of Alzheimer's disease (AD). Presenilins, the major gene products involved in familial AD, are essential for short-and long-term synaptic plasticity in mature neurons as well as for the survival of cortical neurons during aging. Presenilin and nicastrin are both indispensable components of the γ-secretase complex, but it remains unknown whether presenilin regulates synaptic function in a γ-secretase-dependent or γ-secretase-independent manner and whether nicastrin plays similar roles in central synapses. In the current study, we address these questions using an electrophysiological approach to analyze nicastrin conditional knockout (cKO) mice in the hippocampal Schaffer collateral pathway. In these mice, we found that, even at 2 mo of age, deletion of nicastrin in excitatory neurons of the postnatal forebrain using Cre recombinase expressed under the control of the αCaMKII promoter led to deficits in presynaptic short-term plasticity including paired-pulse facilitation and frequency facilitation. Depletion of Ca 2+ in the endoplasmic reticulum mimics and occludes the presynaptic facilitation deficits in nicastrin cKO mice, suggesting that disrupted intracellular Ca 2+ homeostasis underlies the presynaptic deficits. In addition, NMDA receptor-mediated responses and long-term potentiation induced by theta-burst stimulation were decreased in nicastrin cKO mice at 3 mo but not at 2 mo of age. Together, these findings show that, similar to presenilins, nicastrin plays essential roles in the regulation of short-and longterm synaptic plasticity, highlighting the importance of γ-secretase in the function of mature synapses.A lzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and cognitive decline. The majority of familial AD cases are caused by missense mutations in genes encoding presenilin 1 (PS1) and presenilin 2, which are crucial components of the γ-secretase complex responsible for intramembrane cleavages of type I membrane proteins such as Notch. In addition to presenilin (PS), nicastrin (Nct), presenilin enhancer 2 (Pen-2), and anterior pharynx defective 1 (Aph-1) also are required to form the active γ-secretase complex. Nct is a type-1 transmembrane glycoprotein that originally was identified by its ability to form high molecular weight complexes with PS (1). Nct −/− mice die by embryonic day 10.5 and exhibit patterning defects similar to those in embryos lacking PS or Notch (2-7).In the adult brain, genetic studies using conditional genetargeting approaches demonstrated that both PS and Nct are essential for long-term memory and age-dependent neuronal survival (8-12). These findings highlight the importance of γ-secretase in memory and neuronal survival (13), even though γ-secretase-independent activities of PS have been reported also (14). However, Notch is unlikely to be the key mediator of γ-secretase in the adult brain, because Notch1 and Notch2 conditional knockout (cKO)...

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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.…”

Section: Introductionmentioning

confidence: 99%

Loss of RBPj in Postnatal Excitatory Neurons Does Not Cause Neurodegeneration or Memory Impairments in Aged Mice

et al. 2012

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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.

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Two novel mutations of the nicastrin gene in Chinese patients with acne inversa

Cited by 57 publications

References 14 publications

Familial Frontotemporal Dementia-AssociatedPresenilin-1 c.548G>TMutation Causes Decreased mRNA Expression and Reduced Presenilin Function in Knock-In Mice

Familial Frontotemporal Dementia-AssociatedPresenilin-1 c.548G>TMutation Causes Decreased mRNA Expression and Reduced Presenilin Function in Knock-In Mice

Synaptic function of nicastrin in hippocampal neurons

Loss of RBPj in Postnatal Excitatory Neurons Does Not Cause Neurodegeneration or Memory Impairments in Aged Mice

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