Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibit
phase 1 trial,14 because interest remains in developing PPARγ-modulating drugs27 for specific settings,23 and because the impact of TZD-class drugs on the development of mammary cancer initiated by loss of function of the genetic risk factor breast cancer 1, early onset (Brca1) was not ...
Hughes Medical Institute, University of Pennsylvania, Philadelphia, PA, USA Birt–Hogg–Dube´ (BHD) syndrome is an inherited cancer susceptibility disease characterized by skin and kidney tumors, as well as cystic lung disease, which results from loss-of-function mutations in the BHD gene. BHD...
In the ExAC database, CACNA1B is predicted to be extremely intolerant of loss of function and has a pLi score of 0.98.11 Direct Sanger sequencing confirmed whole-exome sequencing findings and showed appropriate segregation of the mutation in the family (Figure 1A). An unaffected sibling (A...
As BICD2 forms dimers, such mutations may also im- pair the cargo binding ability of wild type/mutant BICD2 heterodimers, leading to near complete loss of function as opposed to haploinsufficiency. A loss of function effect in SMALED2 was thought to be unlikely as the Bicd2−/− mouse...
Breast cancer frequently metastasizes to the skeleton, interrupting the normal bone remodeling process and causing bone degradation. Osteolytic lesions are the end result of osteoclast activity; however, osteoclast differentiation and activation are medi
Autosomal dominant adult-onset neuronal ceroid lipofuscinosis (AD-ANCL) is a multisystem disease caused by mutations in the DNAJC5 gene. DNAJC5 encodes Cysteine String Protein-alpha (CSPα), a putative synaptic protein. AD-ANCL has been traditionally considered a lysosomal storage disease based on ...
of folding (ΔΔG) upon mutation, represent an alternate computational strategy for understanding the effects of missense mutations. Most stability predictors directly utilise protein structures to model the change in stability between the wild-type and variant proteins through a scoring function of ...
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Chemically, Nt-acetylation refers to a process that involves the covalent addition of an acetyl group to the free amino group of the α-carbon of the N-terminal residue in a protein. This process is catalyzed by Nt-acetyltransferases (NATs) using acetyl coenzyme A (Ac-CoA) as the main don...