Pitt–Hopkins syndrome: phenotypic and genotypic description of four unrelated patients and structural analysis of corresponding missense mutations

Neurogenetics ◽  
2021 ◽  
Author(s):  
Tingting Zhao ◽  
Georgi Z. Genchev ◽  
Shengnan Wu ◽  
Guangjun Yu ◽  
Hui Lu ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Missense Mutations

scholarly journals Structural analysis of pathogenic missense mutations in GABRA2 and identification of a novel de novo variant in the desensitization gate

2020 ◽  
Vol 8 (7) ◽  
Author(s):  
Alba Sanchis‐Juan ◽  
Marcia A. Hasenahuer ◽  
James A. Baker ◽  
Amy McTague ◽  
Katy Barwick ◽  
...  
Keyword(s):  
Structural Analysis ◽  
De Novo ◽  
Missense Mutations ◽  
De Novo Variant

Update of the spectrum of mucopolysaccharidoses type III in Tunisia: identification of three novel mutations and in silico structural analysis of the missense mutations

2017 ◽  
Vol 13 (4) ◽  
pp. 374-380 ◽  
Author(s):  
Souad Ouesleti ◽  
Maria Francisca Coutinho ◽  
Isaura Ribeiro ◽  
Abdehedi Miled ◽  
Dalila Saidane Mosbahi ◽  
...  
Keyword(s):  
Structural Analysis ◽  
In Silico ◽  
Missense Mutations ◽  
Novel Mutations ◽  
Type Iii

scholarly journals Genetic Epidemiology of Glucose-6-Phosphate Dehydrogenase Deficiency in the Arab World

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
C. George Priya Doss ◽  
Dima R. Alasmar ◽  
Reem I. Bux ◽  
P. Sneha ◽  
Fadheela Dad Bakhsh ◽  
...  
Keyword(s):  
Structural Analysis ◽  
In Silico ◽  
Simulation Analysis ◽  
Arab World ◽  
Arab Countries ◽  
Dynamics Simulation ◽  
Missense Mutations ◽  
Future Prediction ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Mutant Forms

Abstract A systematic search was implemented using four literature databases (PubMed, Embase, Science Direct and Web of Science) to capture all the causative mutations of Glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDD) in the 22 Arab countries. Our search yielded 43 studies that captured 33 mutations (23 missense, one silent, two deletions, and seven intronic mutations), in 3,430 Arab patients with G6PDD. The 23 missense mutations were then subjected to phenotypic classification using in silico prediction tools, which were compared to the WHO pathogenicity scale as a reference. These in silico tools were tested for their predicting efficiency using rigorous statistical analyses. Of the 23 missense mutations, p.S188F, p.I48T, p.N126D, and p.V68M, were identified as the most common mutations among Arab populations, but were not unique to the Arab world, interestingly, our search strategy found four other mutations (p.N135T, p.S179N, p.R246L, and p.Q307P) that are unique to Arabs. These mutations were exposed to structural analysis and molecular dynamics simulation analysis (MDSA), which predicting these mutant forms as potentially affect the enzyme function. The combination of the MDSA, structural analysis, and in silico predictions and statistical tools we used will provide a platform for future prediction accuracy for the pathogenicity of genetic mutations.

Structural analysis of missense mutations in galactokinase 1 (GALK1) leading to galactosemia type-2

2018 ◽  
Vol 119 (9) ◽  
pp. 7585-7598 ◽  
Author(s):  
Sneha P ◽  
Elaheh Ahmad Ebrahimi ◽  
Sara Ahmed Ghazala ◽  
Thirumal Kumar D ◽  
Siva R ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Missense Mutations

scholarly journals Structural analysis of missense mutations occurring in the DNA-binding domain of HSF4 associated with congenital cataracts

2020 ◽  
Vol 4 ◽  
pp. 100015
Author(s):  
Zaiyu Xiao ◽  
Ling Guo ◽  
Yang Zhang ◽  
Liwei Cui ◽  
Yujie Dai ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Dna Binding ◽  
Binding Domain ◽  
Dna Binding Domain ◽  
Missense Mutations ◽  
Congenital Cataracts

scholarly journals Structural analysis of pathogenic missense mutations in GABRA2 and identification of a novel de novo variant in the desensitization gate

2019 ◽  
Author(s):  
Alba Sanchis-Juan ◽  
Marcia A Hasenahuer ◽  
James A Baker ◽  
Amy McTague ◽  
Katy Barwick ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Neuronal Excitability ◽  
Transmembrane Domain ◽  
De Novo ◽  
Structural Information ◽  
Missense Variant ◽  
Epileptic Encephalopathy ◽  
Missense Mutations ◽  
Pathogenic Variants ◽  
Activation Gate

AbstractCys-loop receptors are vital for controlling neuronal excitability in the brain and their dysfunction results in numerous neurological disorders. Recently, six de novo missense variants in GABRA2 gene, a member of this family, have been associated with early infantile epileptic encephalopathy (EIEE) and intellectual disability with seizures. Here, using whole-genome sequencing we identified a de novo missense variant in GABRA2 gene in a patient with EIEE and developmental delay. We perform protein structural analysis of the seven variants and show that all the mutations are in the transmembrane domain, either close to the desensitization gate, the activation gate or in inter-subunit interfaces. Further investigations demonstrated that the majority of pathogenic variants reported are at equivalent positions in other Cys-loop receptors, emphasizing the importance of these residues for the adequate function of the receptor. Also, a comparison of the distribution of the mutations in all the Cys-loop receptors showed that pathogenic variants are more common in the transmembrane helices, more specifically in the M2 helix, highlighting the importance of this segment. Our study expands the clinical spectrum of individuals with pathogenic missense mutations in GABRA2, defines the regions where pathogenic mutations are in the protein structure, and highlights the value of considering sequence, evolutionary, and structural information from other Cys-loop receptors as a strategy for variant interpretation of novel missense mutations in GABRA2.

Molecular and Clinical Investigations on Portuguese Patients with Multiple acyl-CoA Dehydrogenase Deficiency

2019 ◽  
Vol 19 (7) ◽  
pp. 487-493 ◽  
Author(s):  
Bárbara J. Henriques ◽  
Tânia G. Lucas ◽  
Esmeralda Martins ◽  
Ana Gaspar ◽  
Anabela Bandeira ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Dehydrogenase Deficiency ◽  
Molecular Model ◽  
Clinical Effects ◽  
Missense Mutations ◽  
Oral Supplementation ◽  
Bioinformatic Tools ◽  
Secondary Pathology ◽  
Functional Consequences ◽  
Splice Mutations

Background: Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) is a congenital rare metabolic disease with broad clinical phenotypes and variable evolution. This inborn error of metabolism is caused by mutations in the ETFA, ETFB or ETFDH genes, which encode for the mitochondrial ETF and ETF:QO proteins. A considerable group of patients has been described to respond positively to riboflavin oral supplementation, which constitutes the prototypic treatment for the pathology. Objectives: To report mutations in ETFA, ETFB and ETFDH genes identified in Portuguese patients, correlating, whenever possible, biochemical and clinical outcomes with the effects of mutations on the structure and stability of the affected proteins, to better understand MADD pathogenesis at the molecular level. Methods: MADD patients were identified based on the characteristic urinary profile of organic acids and/or acylcarnitine profiles in blood spots during newborn screening. Genotypic, clinical and biochemical data were collected for all patients. In silico structural analysis was employed using bioinformatic tools carried out in an ETF:QO molecular model for the identified missense mutations. Results: A survey describing clinical and biochemical features of eight Portuguese MADD patients was made. Genotype analysis identified five ETFDH mutations, including one extension (p.X618QextX*14), two splice mutations (c.34+5G>C and c.405+3A>T) and two missense mutations (ETF:QO-p.Arg155Gly and ETF:QO-p.Pro534Leu), and one ETFB mutation (ETFβ- p.Arg191Cys). Homozygous patients containing the ETFDH mutations p.X618QextX*14, c.34+5G>C and ETF:QO-p.Arg155Gly, all presented severe (lethal) MADD phenotypes. However, when any of these mutations are in heterozygosity with the known ETF:QO-p.Pro534Leu mild variant, the severe clinical effects are partly and temporarily attenuated. Indeed, the latter destabilizes an ETF-interacting loop, with no major functional consequences. However, the position 155 in ETF:QO is localized at the ubiquinone binding and membrane interacting domain, and is thus expected to perturb protein structure and membrane insertion, with severe functional effects. Structural analysis of molecular models is therefore demonstrated to be a valuable tool to rationalize the effects of mutations in the context of the clinical phenotype severity. Conclusion: Advanced molecular diagnosis, structural analysis and clinical correlations reveal that MADD patients harboring a severe prognosis mutation in one allele can actually revert to a milder phenotype by complementation with a milder mutation in the other allele. However, such patients are nevertheless in a precarious metabolic balance which can revert to severe fatal outcomes during catabolic stress or secondary pathology, thus requiring strict clinical follow-up.

scholarly journals Comparative structural analysis of human Nav1.1 and Nav1.5 reveals mutational hotspots for sodium channelopathies

2021 ◽  
Vol 118 (11) ◽  
pp. e2100066118
Author(s):  
Xiaojing Pan ◽  
Zhangqiang Li ◽  
Xueqin Jin ◽  
Yanyu Zhao ◽  
Gaoxingyu Huang ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Electromechanical Coupling ◽  
Structural Integrity ◽  
Therapeutic Interventions ◽  
Missense Mutations ◽  
Disease Mutations ◽  
Mutational Hotspots ◽  
Cardiac Disorders ◽  
Function Relationship ◽  
Pore Domain

Among the nine subtypes of human voltage-gated sodium (Nav) channels, the brain and cardiac isoforms, Nav1.1 and Nav1.5, each carry more than 400 missense mutations respectively associated with epilepsy and cardiac disorders. High-resolution structures are required for structure–function relationship dissection of the disease variants. We report the cryo-EM structures of the full-length human Nav1.1–β4 complex at 3.3 Å resolution here and the Nav1.5-E1784K variant in the accompanying paper. Up to 341 and 261 disease-related missense mutations in Nav1.1 and Nav1.5, respectively, are resolved. Comparative structural analysis reveals several clusters of disease mutations that are common to both Nav1.1 and Nav1.5. Among these, the majority of mutations on the extracellular loops above the pore domain and the supporting segments for the selectivity filter may impair structural integrity, while those on the pore domain and the voltage-sensing domains mostly interfere with electromechanical coupling and fast inactivation. Our systematic structural delineation of these mutations provides important insight into their pathogenic mechanism, which will facilitate the development of precise therapeutic interventions against various sodium channelopathies.

Sign in / Sign up

Export Citation Format

Share Document