CDKN2A LOF was present in 26% of patients and was associated with inferior PFS (multivariate hazard ratio [MVA-HR] 1.66, 95% CI 1.02–2.63,=0.041) and OS (MVA-HR 2.08, 95% CI 1.21–3.49,=0.0087) when compared to wild-type (WT) patients. These findings held in patients with high ...
功能缺失LOF定义及重要性功能缺失(LossofFunction,LOF)是指基因突变导致基因产物(如蛋白质)功能丧失或降低的现象。LOF突变在单基因病中占据重要地位,是导致疾病发生的主要原因之一。研究LOF突变有助于深入了解单基因病的致病机理,为疾病诊断和治疗提供理论依据。
➢丧失功能(lossoffunction,LOF)是最常见的致病机制，绝大多数单基因遗传病都是因为基因LOF造成的。➢LOF可以是变异造成蛋白结构破坏，也可以是变异造成蛋白剂量减少，即二者都是造成正常的蛋白减少。蛋白结构破坏 蛋白剂量减少 LOF变异类型 蛋白结构改变 起始密码子变异错义变异无义变异移码变异延长变异 剪接位点变异...
Protein levels of NEK3 were abrogated in Patient-1 with biallelic loss-of function (LoF) NEK3 mutations that causes premature stop codon. Subsequence transcriptome analysis revealed that NNMT (nicotinamide N -methyltransferase) and SIRT2 (sirtuin2) was upregulated by NEK3 knockdown in human ...
Methods: We leveraged whole exome sequencing (WES) data to extract carriers of at least one APOC3 LoF variant from 407,669 participants of European ancestry in the UK Biobank and used the Combined Annotation Dependent Depletion (CADD) score to quantify their deleteriousness. We then selected var...
Loss-of-function (LOF) alleles in a PAK kinase impacted protein stability and pathway specificity decreasing filamentous growth and mating phenotypes. In contrast, gain-of-function (GOF) alleles in G-proteins that were hyperactivating induced filamentous growth. Similar amino acid substitutions in G-...
While some dominant mutations will cause disease via LOF (i.e., haploinsufficiency), many will be DN or GOF. Thus, we expect that differences in the structural effects of recessive vs dominant missense mutations should be reflective of the differences between LOF and non-LOF mechanisms....
While there has been much focus on how mutations can disrupt protein structure and thus cause a loss of function (LOF), alternative mechanisms, specifically dominant-negative (DN) and gain-of- function (GOF) effects, are less understood. Here, we investigate the protein-level effects of ...
We identify rare and likely deleterious LoF alleles, including 26 known and 21 predicted severe disease–causing variants, as well as common LoF variants in nonessential genes. We describe functional and evolutionary differences between LoF-tolerant and recessive disease genes and a method for using ...
The molecular mechanisms underlying the genetic basis of RTD pathogenesis are still not fully elucidated; however, LoF/structural variants in genes encoding components of the RAS pathway are a major cause of the disease [8]. Disruption of the RAS leads to defects in the differentiation of proximal...