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Autor: Lander, Eric S

3 záznamů v Medvik Filtry

Článek

Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy

Dvela-Levitt, Moran
Autor Dvela-Levitt, Moran Broad Institute of MIT and Harvard, Cambridge, MA, USA Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Kost-Alimova, Maria
Autor Kost-Alimova, Maria Broad Institute of MIT and Harvard, Cambridge, MA, USA
Emani, Maheswarareddy
Autor Emani, Maheswarareddy Broad Institute of MIT and Harvard, Cambridge, MA, USA Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Kohnert, Eva
Autor Kohnert, Eva Broad Institute of MIT and Harvard, Cambridge, MA, USA Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Thompson, Rebecca
Autor Thompson, Rebecca Broad Institute of MIT and Harvard, Cambridge, MA, USA Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Sidhom, Eriene-Heidi
Autor Sidhom, Eriene-Heidi Broad Institute of MIT and Harvard, Cambridge, MA, USA Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Rivadeneira, Ana
Autor Rivadeneira, Ana Broad Institute of MIT and Harvard, Cambridge, MA, USA Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Sahakian, Nareh
Autor Sahakian, Nareh Broad Institute of MIT and Harvard, Cambridge, MA, USA Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Roignot, Julie
Autor Roignot, Julie Broad Institute of MIT and Harvard, Cambridge, MA, USA Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Papagregoriou, Gregory
Autor Papagregoriou, Gregory Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus

Cell. 2019 ; 178 (3) : 521-535.e23. [pub] 20190725

ISSN 1097-4172
Medvik
Zdroj

Intracellular accumulation of misfolded proteins causes toxic proteinopathies, diseases without targeted therapies. Mucin 1 kidney disease (MKD) results from a frameshift mutation in the MUC1 gene (MUC1-fs). Here, we show that MKD is a toxic proteinopathy. Intracellular MUC1-fs accumulation activated the ATF6 unfolded protein response (UPR) branch. We identified BRD4780, a small molecule that clears MUC1-fs from patient cells, from kidneys of knockin mice and from patient kidney organoids. MUC1-fs is trapped in TMED9 cargo receptor-containing vesicles of the early secretory pathway. BRD4780 binds TMED9, releases MUC1-fs, and re-routes it for lysosomal degradation, an effect phenocopied by TMED9 deletion. Our findings reveal BRD4780 as a promising lead for the treatment of MKD and other toxic proteinopathies. Generally, we elucidate a novel mechanism for the entrapment of misfolded proteins by cargo receptors and a strategy for their release and anterograde trafficking to the lysosome.

Článek

Development and Validation of a Mass Spectrometry-Based Assay for the Molecular Diagnosis of Mucin-1 Kidney Disease

The Journal of molecular diagnostics. 2016 ; 18 (4) : 566-71. [pub] 20160505

J Mol Diagn
ISSN 1943-7811
Medvik
Zdroj

Mucin-1 kidney disease, previously described as medullary cystic kidney disease type 1 (MCKD1, OMIM 174000), is an autosomal dominant tubulointerstitial kidney disease recently shown to be caused by a single-base insertion within the variable number tandem repeat region of the MUC1 gene. Because of variable age of disease onset and often subtle signs and symptoms, clinical diagnosis of mucin-1 kidney disease and differentiation from other forms of hereditary kidney disease have been difficult. The causal insertion resides in a variable number tandem repeat region with high GC content, which has made detection by standard next-generation sequencing impossible to date. The inherently difficult nature of this mutation required an alternative method for routine detection and clinical diagnosis of the disease. We therefore developed and validated a mass spectrometry-based probe extension assay with a series of internal controls to detect the insertion event using 24 previously characterized positive samples from patients with mucin-1 kidney disease and 24 control samples known to be wild type for the variant. Validation results indicate an accurate and reliable test for clinically establishing the molecular diagnosis of mucin-1 kidney disease with 100% sensitivity and specificity across 275 tests called.

MeSH
diagnostické techniky molekulární * MeSH
genotyp MeSH
hmotnostní spektrometrie metody normy MeSH
lidé MeSH
mucin 1 genetika MeSH
mutace * MeSH
polycystické ledviny autozomálně dominantní diagnóza genetika MeSH
průběh práce MeSH
reprodukovatelnost výsledků MeSH
senzitivita a specificita MeSH
Check Tag
lidé MeSH
Publikační typ
časopisecké články MeSH

Článek

A genetic linkage map of the laboratory rat, Rattus norvegicus

Nature genetics. 1995 ; 9 (1) : 63-69.

Nat Genet
ISSN 1061-4036
Medvik
Zdroj

We report the construction of the first complete genetic linkage map of the laboratory rat. By testing 1171 simple sequence length polymorphisms (SSLPs), we have identified 432 markers that show polymorphisms between the SHR and BN rat strains and mapped them in a single (SHR x BN) F2 intercross. The loci define 21 large linkage groups corresponding to the 21 rat chromosomes, together with a pair of nearby markers on chromosome 9 that are not linked to the rest of the map. Because 99.5% of the markers fall into one of the 21 large linkage groups, the maps appear to cover the vast majority of the rat genome. The availability of the map should facilitate whole genome scans for genes underlying qualitative and quantitative traits relevant to mammalian physiology and pathobiology.

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