scholarly journals Tracing the genetics of neurological disease to the mutation-directed addition of single hydrogen bonds

2021 ◽  
Author(s):  
Xiaoming Zhou ◽  
Kyuto Tashiro ◽  
Lily Sumrow ◽  
Lillian Sutherland ◽  
Glen Liszczak ◽  
...  
Keyword(s):  
Hydrogen Bond ◽  
Amino Acid ◽  
Protein Function ◽  
Low Complexity ◽  
Peptide Backbone ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Coding Regions ◽  
Sequence Complexity ◽  
Recurrent Mutations

AbstractMutations causative of neurological and neurodegenerative disease can occur in coding regions that specify protein domains of low sequence complexity. These autosomal dominant mutations can be idiosyncratic in their recurrent appearance at the same amino acid. Here we report studies of recurrent mutations in proline residues located within low complexity (LC) domains associated with the neurofilament light chain protein, the microtubule-associated tau protein, and the heterogeneous nuclear RNPA2 protein. All such mutations manifest their effects by directing formation of variant proteins endowed with the addition of a single, main chain hydrogen bond specified by the variant amino acid replacing proline. Here we show that methylation of the peptide backbone nitrogen atom associated with these variant amino acids eliminates the aberrant hydrogen bond and restores normal protein function.

scholarly journals G-quadruplex-forming sequences as potential drivers of genetic diversity in primate protein coding genes

2020 ◽  
Author(s):  
Manuel Jara-Espejo ◽  
Sergio Roberto Peres Line
Keyword(s):  
Genetic Diversity ◽  
Amino Acid ◽  
Protein Function ◽  
Evolutionary Dynamics ◽  
Regulatory Elements ◽  
Evolutionary Trend ◽  
Protein Coding ◽  
Coding Regions ◽  
Mutational Pattern ◽  
Species Specific

ABSTRACTWhile non-coding G-quadruplexes (G4s) act as conserved regulatory elements when located in gene promoter and splice sites, the G4 evolutionary conservation in protein coding regions have been low explored. To address the evolutionary dynamics acting on coding G4, we mapped and characterized potential G4-forming sequences across twenty-four primate’s gene orthologous. We found that potentially more stable G4 motifs exist in coding regions following a species-specific trend. Moreover, these motifs depicted the least conserved sites across primates at both the DNA and amino acid levels and are characterized by an indel-rich mutational pattern. This trend was not observed for less stable G4 motifs. A deeper analysis revealed that [G>=3N1]4 motifs, depicting potentially most stable G4s, were associated with the lowest conservation and highest indel frequencies. This mutational pattern was more evident when G4-associated amino acid regions were analyzed. We discuss the possibility of an overall conservation of less/moderate stability G4, while more stable G4 may be preserved or arises in a species-specific manner, which may explain their low conservation. Since structure-prone motifs, including G4, have the potential to induce genomic instability, this evolutionary trend may contribute to avoid broad deleterious effects driven by stable G4 on protein function while promoting genetic diversity across close-related species.

Aspects of tuberous sclerosis complex (TSC) protein function in the brain

2003 ◽  
Vol 31 (3) ◽  
pp. 579-583 ◽  
Author(s):  
V. Ramesh
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Protein Function ◽  
Direct Interaction ◽  
Wild Type ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Dominant Disease ◽  
The Central Nervous System ◽  
Cortical Tubers

Tuberous sclerosis complex (TSC), an autosomal dominant disease caused by mutations in either TSC1 or TSC2, is characterized by the development of hamartomas in a variety of organs. Concordant with the tumour-suppressor model, loss of heterozygosity (LOH) is known to occur in these hamartomas at both TSC1 and TSC2 loci. LOH has been documented in renal angiomyolipomas, but loss of the wild-type allele in cortical tubers appears very uncommon. We analysed 24 hamartomas from 10 patients for second-hit mutations by several methods, and found no evidence for the inactivation of the second allele in many of the central nervous system (CNS) lesions, including tumours that appear to be clonally derived. We believe that somatic mutations in TSC1 and TSC2 resulting in the loss of wild-type alleles may not be necessary in some tumour types, and other mechanisms may contribute to tumorigenesis in this setting. We have shown that hamartin interacts with neurofilament light chain (NF-L) and could integrate the neuronal cytoskeleton through its direct interaction with NF-L and ERM (ezrin/radixin/moeisin) proteins. Our unpublished work further documents the binding of tuberin with Pam, a protein associated with c-Myc, which is enriched in brain. All these observations suggest that the tuberin–hamartin complex is likely to have distinct functions in the CNS.

Hubsm: A Novel Amino Acid Substitution Matrix for Comparing Hub Proteins

2017 ◽  
Vol 7 (8) ◽  
pp. 212
Author(s):  
Renganayaki G. ◽  
Achuthsankar S. Nair
Keyword(s):  
Amino Acid ◽  
Amino Acid Substitution ◽  
Low Complexity ◽  
Database Search ◽  
Substitution Matrix ◽  
Compositional Bias ◽  
Sequence Alignments ◽  
Amino Acid Substitution Matrix ◽  
Alignment Algorithms ◽  
Hub Proteins

Sequence alignment algorithms and  database search methods use BLOSUM and PAM substitution matrices constructed from general proteins. These de facto matrices are not optimal to align sequences accurately, for the proteins with markedly different compositional bias in the amino acid.   In this work, a new amino acid substitution matrix is calculated for the disorder and low complexity rich region of Hub proteins, based on residue characteristics. Insights into the amino acid background frequencies and the substitution scores obtained from the Hubsm unveils the  residue substitution patterns which differs from commonly used scoring matrices .When comparing the Hub protein sequences for detecting homologs,  the use of this Hubsm matrix yields better results than PAM and BLOSUM matrices. Usage of Hubsm matrix can be optimal in database search and for the construction of more accurate sequence alignments of Hub proteins.

Increased frequency of proinflammatory CD4 T cells and pathological levels of serum neurofilament light chain in adult drug‐resistant epilepsy

Epilepsia ◽  
2020 ◽  
Author(s):  
Oumarou Ouédraogo ◽  
Rose‐Marie Rébillard ◽  
Hélène Jamann ◽  
Victoria Hannah Mamane ◽  
Marie‐Laure Clénet ◽  
...  
Keyword(s):  
T Cells ◽  
Light Chain ◽  
Cd4 T Cells ◽  
Drug Resistant ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Drug Resistant Epilepsy

scholarly journals Plasma NfL levels and longitudinal change rates in C9orf72 and GRN-associated diseases: from tailored references to clinical applications

2021 ◽  
pp. jnnp-2021-326914
Author(s):  
Dario Saracino ◽  
Karim Dorgham ◽  
Agnès Camuzat ◽  
Daisy Rinaldi ◽  
Armelle Rametti-Lacroux ◽  
...  
Keyword(s):  
Single Molecule ◽  
Light Chain ◽  
Rate Of Change ◽  
Longitudinal Change ◽  
Youden Index ◽  
Clinical Genetic ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Link Type ◽  
Therapeutic Trials

ObjectiveNeurofilament light chain (NfL) is a promising biomarker in genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We evaluated plasma neurofilament light chain (pNfL) levels in controls, and their longitudinal trajectories in C9orf72 and GRN cohorts from presymptomatic to clinical stages.MethodsWe analysed pNfL using Single Molecule Array (SiMoA) in 668 samples (352 baseline and 316 follow-up) of C9orf72 and GRN patients, presymptomatic carriers (PS) and controls aged between 21 and 83. They were longitudinally evaluated over a period of >2 years, during which four PS became prodromal/symptomatic. Associations between pNfL and clinical–genetic variables, and longitudinal NfL changes, were investigated using generalised and linear mixed-effects models. Optimal cut-offs were determined using the Youden Index.ResultspNfL levels increased with age in controls, from ~5 to~18 pg/mL (p<0.0001), progressing over time (mean annualised rate of change (ARC): +3.9%/year, p<0.0001). Patients displayed higher levels and greater longitudinal progression (ARC: +26.7%, p<0.0001), with gene-specific trajectories. GRN patients had higher levels than C9orf72 (86.21 vs 39.49 pg/mL, p=0.014), and greater progression rates (ARC:+29.3% vs +24.7%; p=0.016). In C9orf72 patients, levels were associated with the phenotype (ALS: 71.76 pg/mL, FTD: 37.16, psychiatric: 15.3; p=0.003) and remarkably lower in slowly progressive patients (24.11, ARC: +2.5%; p=0.05). Mean ARC was +3.2% in PS and +7.3% in prodromal carriers. We proposed gene-specific cut-offs differentiating patients from controls by decades.ConclusionsThis study highlights the importance of gene-specific and age-specific references for clinical and therapeutic trials in genetic FTD/ALS. It supports the usefulness of repeating pNfL measurements and considering ARC as a prognostic marker of disease progression.Trial registration numbersNCT02590276 and NCT04014673.

Sign in / Sign up

Export Citation Format

Share Document