PMID- 38356142
OWN - NLM
STAT- Publisher
LR  - 20240215
IS  - 1538-0254 (Electronic)
IS  - 0739-1102 (Linking)
DP  - 2024 Feb 14
TI  - Association of epilepsy and neurological impairments with homozygous recessive 
      missense mutations found in the genes responsible for ganglioside biosynthesis 
      (ST3GAL5) and calcium voltage-gated channels (CACNA1H) - insights through 
      molecular dynamic simulations.
PG  - 1-12
LID - 10.1080/07391102.2024.2314751 [doi]
AB  - With over 2.2 million cases, the incidence rate of epilepsy in Pakistan is far 
      higher than the rest of the world due primarily to the frequent, traditionally 
      imposed cousin marriages. In the present study, comprehensive whole exome 
      sequencing (WES) analyses of a three-generation family with four affected members 
      presenting 'unexplained' childhood absence epilepsy (CAE), seizures and dementia, 
      was performed in a quest to identify heritable, epilepsy-causal gene variants to 
      better aid in carrier screening and genetic counselling. The WES data was 
      generated, analyzed, and validated through Sanger's sequencing, molecular dynamic 
      simulation (MDS) analysis, and molecular mechanics with generalized Born and 
      surface area solvation (MM/GBSA) studies. Two homozygous recessive, missense 
      mutations in ST3GAL5 (c.311A > G, p. His104Arg) and CACNA1H (c.6230G > A, p. 
      Arg2077His) genes, earlier regarded as benign or of uncertain significance, have 
      been identified as a potential etiology. Comparative MDS and free binding energy 
      calculations revealed substantial structural perturbations in mutant forms of 
      ST3GAL5 leading to decreased binding and reduced catalytic activity of the 
      p.His104Arg and two other functional variants (p.Val74Glu and p.Arg288Ter) when 
      compared with wild type. Our findings reinforce that WES analyses may uncover 
      'hidden', heritable variants and together with MDS and MM/GBSA may provide 
      plausible clues to answer the unexplained causes of epilepsy for an effective 
      management and better patient outcome. Further, revisit of epilepsy-associated 
      mutational landscape in population context is imperative as the variants with 
      'benign' tags may turn out to be 'non-benign', when exist in combination with 
      other benign.Communicated by Ramaswamy H. Sarma.
FAU - Abid, Rizwan
AU  - Abid R
AD  - School of Biochemistry and Biotechnology, University of the Punjab, Lahore, 
      Pakistan.
FAU - Nisar, Haseeb
AU  - Nisar H
AD  - Department of Life-Sciences, University of Management and Technology, Lahore, 
      Pakistan.
FAU - Chaudhary, Safee Ullah
AU  - Chaudhary SU
AD  - Biomedical Informatics & Engineering Research Laboratory, Department of 
      Life-Sciences, Syed Babar Ali School of Science and Engineering, Lahore 
      University of Management Sciences, Lahore, Pakistan.
FAU - Hamid, Maham
AU  - Hamid M
AD  - Biomedical Informatics & Engineering Research Laboratory, Department of 
      Life-Sciences, Syed Babar Ali School of Science and Engineering, Lahore 
      University of Management Sciences, Lahore, Pakistan.
FAU - Sahibzada, Kashif Iqbal
AU  - Sahibzada KI
AD  - Department of Health Professional Technologies, The University of Lahore, Lahore, 
      Pakistan.
FAU - Firdous, Safia
AU  - Firdous S
AD  - School of Biochemistry and Biotechnology, University of the Punjab, Lahore, 
      Pakistan.
AD  - Faculty of Rehabilitation and Allied Health Sciences, Riphah International 
      University, Lahore, Pakistan.
FAU - Mudassar, Muhammad
AU  - Mudassar M
AD  - COMSATS University, Islamabad, Pakistan.
FAU - Sadaf, Saima
AU  - Sadaf S
AD  - School of Biochemistry and Biotechnology, University of the Punjab, Lahore, 
      Pakistan.
LA  - eng
PT  - Journal Article
DEP - 20240214
PL  - England
TA  - J Biomol Struct Dyn
JT  - Journal of biomolecular structure & dynamics
JID - 8404176
SB  - IM
OTO - NOTNLM
OT  - Brain gangliosides
OT  - calcium ion channels
OT  - drug targets
OT  - missense variants
OT  - molecular docking
OT  - whole exome sequencing
EDAT- 2024/02/15 06:43
MHDA- 2024/02/15 06:43
CRDT- 2024/02/15 00:11
PHST- 2024/02/15 06:43 [medline]
PHST- 2024/02/15 06:43 [pubmed]
PHST- 2024/02/15 00:11 [entrez]
AID - 10.1080/07391102.2024.2314751 [doi]
PST - aheadofprint
SO  - J Biomol Struct Dyn. 2024 Feb 14:1-12. doi: 10.1080/07391102.2024.2314751.