Characterization of a Novel Mutation in the NCSTN Gene in a Large Chinese Family with Acne Inversa

Zhang, Shide; Meng, Jin Guo; Jiang, Miao; Zhao, Jingjun

doi:10.2340/00015555-2259

Cited by 15 publications

(10 citation statements)

References 12 publications

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“…Examining the distribution of sequence variants in NCSTN , no predilection could be identified pertaining to any specific protein domain or component of the nicastrin protein. Four of the six identified missense sequence variants were located adjacent to or within the Lid protein domain, which is proposed to be a vital binding site for nicastrin . In fact, the only missense variant with confirmed decreased levels of Notch intracellular domain (ICD) involves a missense mutation in exon 6, within the Lid protein domain .…”

Section: Resultsmentioning

confidence: 99%

“…Forty‐one individual sequence variants were identified encompassing the NCSTN , PSEN1 , PSENEN and PSTPIP1 genes, coding for nicastrin, presenilin 1, presenilin enhancer 2 and proline–serine–threonine phosphatase‐interacting protein 1, respectively . The types of sequence variants encompassed heterozygous missense mutations (nine variants), splice‐site mutations (nine variants), an insertion resulting in frameshift (one variant) and 19 variants resulting in premature termination codons or protein truncation . Three variants involved increased numbers of CCTG repeats the promoter region of PSTPIP1 .…”

Section: Resultsmentioning

confidence: 99%

“…Identification of < 20% of the identified variants (eight of 41) involved protein or functional studies examining mRNA, or protein studies of components of the γ‐secretase complex (Table ). An additional four variants (all missense variants) had accompanying protein studies looking at Notch ICD as a proxy for γ‐secretase function. Only one missense variant in the Lid domain of nicastrin ( NCSTN c.647A>C) demonstrated impaired Notch ICD signalling .…”

Section: Discussionmentioning

confidence: 99%

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A systematic review and critical evaluation of reported pathogenic sequence variants in hidradenitis suppurativa

et al. 2017

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Hidradenitis suppurativa (HS) is a severe chronic inflammatory disorder characterized by recurrent painful deep-seated nodules with a predilection to the apocrine-bearing areas of skin. A minority of cases of HS are due to mutations in the γ-secretase complex. Contention exists surrounding the pathogenicity of sequence variants and their effects upon Notch signalling. This systematic review was registered with PROSPERO (CRD42016041425) and was conducted in line with the PRISMA statement. Eligibility criteria for this review included published case reports, case series and reviews that identified sequence variants or protein or functional studies from patients with HS. Sixty-two articles were identified reporting a total of 41 sequence variants - heterozygous missense (nine), splice site (nine), insertion resulting in frameshift (one), premature termination codon (19) and promoter region PSTPIP1 (three) - with 18 associated protein or functional studies. The American College of Medical Genetics and Genomics standards and guidelines on the interpretation of sequence variants were applied to each identified variant to assess evidence for pathogenicity. Twenty-three variants were assessed as likely pathogenic, 17 of uncertain significance and one benign. The large number of variants of 'uncertain significance' is largely due to the variable number of functional studies. Four studies used Notch as a proxy for γ-secretase function, with conclusions of nonpathogenicity based on the assumption of Notch signalling as the sole pathogenic process. The role of Notch-independent signalling mechanisms requires further research. Limitations to this study include identification of variants of Mendelian inheritance and not complex polygenic traits.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A systematic review and critical evaluation of reported pathogenic sequence variants in hidradenitis suppurativa

et al. 2017

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“…We performed an NCBI-Pubmed search using the terms 'hidradenitis suppurativa' and 'mutation', and all reported studies were retrieved (13,9,(14)(15)(16)5,(17)(18)(19)(20)(21)10,(22)(23)(24)(25)(26)6).…”

Section: Identification Of Reported Hs-linked Genetic Mutations and Fmentioning

confidence: 99%

Analysis of hidradenitis suppurativa–linked mutations in four genes and the effects of PSEN1-P242LfsX11 on cytokine and chemokine expression in macrophages

Peng

Taiclet

et al. 2018

Human Molecular Genetics

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Hidradenitis suppurativa (HS), or acne inversa, is a chronic inflammatory skin disorder characterized clinically with acne-like lesions in apocrine gland–bearing skin, follicular occlusion and recurrent inflammation. Thirty-four unique mutations in patients with HS have been found in three genes encoding the γ-secretase complex: nicastrin (NCSTN), presenilin 1 (PSEN1), presenilin enhancer 2 (PSENEN) and in POGLUT1, an endoplasmic reticulum O-glucosyltransferase involved in Notch signaling. We have carried out a system review and have performed a functional analysis of the 34 unique reported HS-linked mutations in NCSTN, PSEN1, PSENEN and POGLUT1. We have also examined the effects of the HS-linked PSEN1-P242LfsX11 mutation on cytokine and chemokine expression in macrophages. Mutations in NCSTN are predicted to cause loss of function, to result in loss of transmembrane (TM) domain, to affect NCSTN substrate recruitment sites, to cause loss or creation of new ligand binging sites and to alter post-translational modifications and disulfide bonds. PSEN1-P242LfsX11 occurs at the opposite side of TM5 from Alzheimer’s disease–linked PSEN1 mutations. All of the PSENEN mutations occur on TM regions that are predicted to disrupt membrane function. POGLUT1 mutations lead to an early termination of protein synthesis and are predicted to affect ligand binding function. In addition, PSEN1-P242LfsX11 mediates cytokine and chemokine expression and prolongs tumor necrosis factor α production on the inflammatory processes in THP-1 cells and phorbol-12-myristate-13-acetate–differentiated macrophages in response to lipopolysaccharide stimulation. These in silico analyses are instructive for functional studies of the HS-linked mutations. The PSEN1-P242LfsX11 mutation mediates cytokine and chemokine expression in macrophages.

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“…In addition to the Alzheimer’s disease-related functions, nicastrin has been reported to be relevant for breast cancer1112 and acne inversa1314. However, the role of nicastrin in the γ-secretase complex is controversial.…”

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confidence: 99%

High-efficient production and biophysical characterisation of nicastrin and its interaction with APPC100

Yang

Labahn

2017

Sci Rep

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Nicastrin, the largest member among the four components of the γ-secretase complex, has been identified to be the substrate recognizer for the proteolytic activity of the complex. Here we report that full-length human nicastrin (hNCT) can be obtained by heterologous expression in E. coli. Milligram quantities of the target protein are purified in a two-step purification protocol using affinity chromatography followed by SEC. The FOS-choline 14 purified tetrameric hNCT exhibits a proper folding with 31% α-helix and 23% β-sheet content. Thermal stability studies reveal stable secondary and tertiary structure of the detergent purified hNCT. A physical interaction between nicastrin and the γ-secretase substrate APPC100 confirmed the functionality of hNCT as a substrate recognizer.

show abstract

Characterization of a Novel Mutation in the NCSTN Gene in a Large Chinese Family with Acne Inversa

Cited by 15 publications

References 12 publications

A systematic review and critical evaluation of reported pathogenic sequence variants in hidradenitis suppurativa

A systematic review and critical evaluation of reported pathogenic sequence variants in hidradenitis suppurativa

Analysis of hidradenitis suppurativa–linked mutations in four genes and the effects of PSEN1-P242LfsX11 on cytokine and chemokine expression in macrophages

High-efficient production and biophysical characterisation of nicastrin and its interaction with APPC100

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