CRISPR activation to characterize splice-altering variants in easily accessible cells

Terkelsen, Thorkild; Mikkelsen, Nanna Steengaard; Bak, Ebbe Norskov; Vad-Nielsen, Johan; Blechingberg, Jenny; Weiss, Simone; Drue, Simon Opstrup; Andersen, Henning; Andresen, Brage Storstein; Bak, Rasmus O.; Jensen, Uffe Birk

doi:10.1016/j.ajhg.2023.12.024

Cited by 7 publications

(1 citation statement)

References 48 publications

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“…Significant advances in molecular biology and bio-organic chemistry have changed a new drug research paradigm to treat various pathologies. Cell biology methods allow the reprogramming of specialized differentiated cells to return them to their native state [1,2]. Several dipeptides have been separated from the thymus extract and tested for immunoregulating properties [3].…”

Section: Introductionmentioning

confidence: 99%

The First Reciprocal Activities of Chiral Peptide Pharmaceuticals: Thymogen and Thymodepressin, as Examples

Deigin,

Linkova,

Vinogradova

et al. 2024

IJMS

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Peptides show high promise in the targeting and intracellular delivery of next-generation biotherapeutics. The main limitation is peptides’ susceptibility to proteolysis in biological systems. Numerous strategies have been developed to overcome this challenge by chemically enhancing the resistance to proteolysis. In nature, amino acids, except glycine, are found in L- and D-enantiomers. The change from one form to the other will change the primary structure of polypeptides and proteins and may affect their function and biological activity. Given the inherent chiral nature of biological systems and their high enantiomeric selectivity, there is rising interest in manipulating the chirality of polypeptides to enhance their biomolecular interactions. In this review, we discuss the first examples of up-and-down homeostasis regulation by two enantiomeric drugs: immunostimulant Thymogen (L-Glu-L-Trp) and immunosuppressor Thymodepressin (D-Glu(D-Trp)). This study shows the perspective of exploring chirality to remove the chiral wall between L- and D-biomolecules. The selected clinical result will be discussed.

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Section: Introductionmentioning

confidence: 99%

The First Reciprocal Activities of Chiral Peptide Pharmaceuticals: Thymogen and Thymodepressin, as Examples

Deigin,

Linkova,

Vinogradova

et al. 2024

IJMS

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Hailey‐Hailey Disease Caused by a Novel Deep Intronic Variant in ATP2C1

Blechingberg,

Terkelsen,

Jensen

et al. 2024

American J of Med Genetics Pt A

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Hailey‐Hailey disease (OMIM#169600) is an autosomal dominantly inherited genodermatosis characterized by erosions in the flexural areas of the body. Hailey‐Hailey disease is caused by variants in ATP2C1, but for ~10% of the patients, no causative variant is found in the coding region of ATP2C1. We aimed to determine the genetic cause of Hailey‐Hailey disease in a family without a variant in the coding areas of ATP2C1. By genome sequencing and analysis of all exon and intron sequences of ATP2C1, we identified the variant c.532‐560 T>G (NM_014382.5) in intron 7 of ATP2C1. The variant is predicted by in silico tools to create a new deep intronic donor splice site. Segregation analysis detected the variant in the three affected family members. RNA sequencing confirmed that the variant creates a new deep intronic donor splice site that gives rise to an alternative exon. The identified deep‐intronic variant in ATP2C1 is the likely cause of Hailey‐Hailey disease. This is to our knowledge the first report of a deep‐intronic variant as the cause of Hailey‐Hailey disease, which shows that the analysis of the intronic sequences of ATP2C1 could increase the genetic diagnostic yield for Hailey‐Hailey disease patients.

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