Missense mutation of the last nucleotide of exon 1 (G-&gt;C) of   globin gene not only leads to undetectable mutant peptide and transcript but also interferes with the expression of wild allele

Agarwal, Neeraj; Kutlar, Ferdane; Mojica-Henshaw, Mariluz P.; Ou, Ching Nan; Gaikwad, Amos; Reading, N. Scott; Bailey, Lakeia; Kutlar, Abdullah; Prchal, Josef T.

doi:10.3324/haematol.11543

Cited by 9 publications

(9 citation statements)

References 5 publications

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“…In other cases, exon skipping can cause a frameshift resulting in aberrant mRNA that is degraded by nonsense-mediated RNA decay, making the abnormal transcript hard to detect [9]. Interestingly, this is the case for most aberrant CDH1 transcripts associated to HDGC [10].…”

Section: Introductionmentioning

confidence: 93%

The germline CDH1 c.48 G > C substitution contributes to cancer predisposition through generation of a pro-invasive mutation

Zhang¹,

Xiao²,

Ruggeri³

et al. 2014

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Section: Introductionmentioning

confidence: 93%

The germline CDH1 c.48 G > C substitution contributes to cancer predisposition through generation of a pro-invasive mutation

Zhang¹,

Xiao²,

Ruggeri³

et al. 2014

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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“…In contrast, we describe the identification of both transcripts resulting from a single heterozygous novel splice site mutation. Substitutions at the last nucleotide of an exon have been reported to disrupt normal splicing (11)(12)(13). The possibility of digenic pathogenicity between KRT1 and KRT9 is also apparent.…”

Section: Resultsmentioning

confidence: 99%

“…Elesclomol-copper complexes can induce oxidative stress and cell death by disruption of the mitochondrial respiration chain or by indirect nonmitochondrial formation of reactive oxygen species (ROS) (7-10). Alternatively, (unbound) copper is required for melanoma cell signalling and tumorigenesis (11). In this context, we have made an interesting observation.…”

Section: Experimental Rationalementioning

confidence: 88%

Next‐generation sequencing detection and characterization of a heterozygous novel splice junction mutation in the 2B domain of KRT1 in a family with diffuse palmoplantar keratoderma

Banerjee

Ren

Wei

et al. 2015

Experimental Dermatology

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efficient (2,4,6). During the development of dendrites, a-MSH elevates the cAMP levels which inhibit PI3-kinase and GTPases activity, resulting in dendrite formation and elongation (5,(12)(13)(14). Therefore, to determine the effect of GF1 on a cAMP-induced signalling pathway related to dendricity in melanocytes, we performed Western blotting and a pull-down assay using forskolin, which is a direct cAMP-elevating agent. GF1 did not affect the forskolininduced dephosphorylation of PI3K (Fig. 2b). However, it significantly reduced forskolin-induced GTP-Rac1, GTP-Cdc42 and reversed inhibition of GTP-Rho, resulting in dendrite retraction. The same effects were also observed in melan-A cells, an immortalized melanocytes, which are another cell model for general use of melanogenesis studies ( Figure S2). Interestingly, however, the intracellular melanin level and tyrosinase expression were increased by GF1, although GF1 reduced extracellular melanin level. These results suggested the presence of a negative feedback loop, whereby the inhibition of extracellular melanin secretion by blocking the phosphorylation of PI3K and regulating GTP-binding proteins leads to hyperactivation of cAMP/PKA signal pathway resulting in upregulation of tyrosinase expression (2-5,12). Collectively, while GF1 stimulated intracellular melanin level and tyrosinase expression, it is clear that GF1 inhibited melanosome transfer by blocking dendrite formation and interfering with dendrite maintenance resulting in reduced extracellular melanin secretion. ConclusionsMelanosome transfer and melanocyte dendrites are key elements in melanin release. A compound that blocks this process would be suitable for use as an antimelanogenic agent. Our results indicate that GF1 reduced extracellular melanin levels and inhibited dendrite formation and elongation, by affecting GTPases, including Rac1, Rho and Cdc42. These results together suggest that GF1 could be a novel skin-whitening agent. AcknowledgementsJH Kim designed the study, performed the research, analysed the data and wrote the paper, EJ Baek and EJ Lee performed the research and analysed the data, MH Yeom and JS Park contributed essential reagents, DC Bennett contributed the melan-a cells for the study, KW Lee and NJ Kang supervised the study. This work was supported by the Interrelated Development Program (R-0000452) of Inter-Economic Regions, Ministry for Knowledge Economy, Republic of Korea. This work was also supported by a National Research Foundation of Korea grant funded by the Korean government (No. 2010-0029233). Conflict of interestThe authors declare no conflict of interest. Supporting InformationAdditional supporting data may be found in the supplementary information of this article. Data S1. Experimental design. Figure S1. Effects of GF1 on cell proliferation in B16F10 cells and melan-a melanocytes. Figure S2. Effects of GF1 on cAMP-induced signaling pathways related to dendricity in melan-a melanocytes. Letter to the Editor keratin-encoding gene, KRT1. We report a heterozygous novel ...

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“…Substitution mutations at this position could also lead to the skipping of more than one exon [7]. In some cases, exon skipping causes a frameshift, the aberrant mRNA is degraded by nonsense-mediated RNA decay, and the abnormal transcript is hard to detect [5]. In other cases, the aberrant splicing products are relatively stable, and an abnormal PCR band is observed after RT-PCR [8].…”

Section: Introductionmentioning

confidence: 96%

“…Substitutions at the last nucleotide of an exon have been reported to disrupt the normal splicing and lead to the deletion of the exon because the mutation coincides with the -1 position of the donor splice site [5,6]. Substitution mutations at this position could also lead to the skipping of more than one exon [7].…”

Section: Introductionmentioning

confidence: 97%

BRCA1 R71K missense mutation contributes to cancer predisposition by increasing alternative transcript levels

Zhang

Chen

Bacares

et al. 2011

Breast Cancer Res Treat

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Mutation screening of the breast and ovarian cancer predisposition genes BRCA1 and BRCA2 is becoming an increasingly important part of clinical practice. Classification of rare non-truncating sequence variants in the BRCA1 and BRCA2 genes is problematic because it is not known whether these subtle changes alter function sufficiently to predispose cells to cancer development. The BRCA1 331G > A substitution mutation, which occurs at the last nucleotide of exon 5, results in an Arg-to-Lys change at codon 71 (R71K). cDNA analysis indicated that the R71K mutation significantly increases the level of a transcript, characterized by a 22 bp deletion in exon 5, which putatively produces a truncated BRCA1 protein of 63 amino acids. The mutation completely abolishes normal splicing as the mutant allele does not generate any normal transcript. Analysis of a tumor specimen indicates loss of heterozygosity. These results support the conclusion that BRCA1 331G > A (R71K) is a deleterious mutation.

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Missense mutation of the last nucleotide of exon 1 (G->C) of globin gene not only leads to undetectable mutant peptide and transcript but also interferes with the expression of wild allele

Cited by 9 publications

References 5 publications

The germline CDH1 c.48 G > C substitution contributes to cancer predisposition through generation of a pro-invasive mutation

The germline CDH1 c.48 G > C substitution contributes to cancer predisposition through generation of a pro-invasive mutation

Next‐generation sequencing detection and characterization of a heterozygous novel splice junction mutation in the 2B domain of KRT1 in a family with diffuse palmoplantar keratoderma

BRCA1 R71K missense mutation contributes to cancer predisposition by increasing alternative transcript levels

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