Exome sequencing and molecular dynamics simulation characterizes a compound heterozygous GCDH missense variant leading to glutaric aciduria type 1 in a paediatric patient from Jammu and Kashmir, India
Por:
Mir, YR, Agrahari, AK, Choudhary, A, Hassan, A, Taneja, AK, Zenteno, JC, Montes-Almanza, L, Rusmini, M, Namba, K, Banday, AZ, Kuchay, RAH
Publicada:
1 mar 2025
Resumen:
Glutaric Aciduria Type 1 (GA1) is a rare autosomal recessive metabolic disorder caused by mutations in the gene GCDH, leading to deficiency of the enzyme glutarylCoA dehydrogenase. This study reports a case of GA1 in a 3year-old male from Jammu and Kashmir, India, presenting with a compound heterozygous mutation in the GCDH. Whole exome sequencing (WES) and molecular dynamics simulations were employed to investigate the genetic and structural basis of GA1 in the proband. Clinical evaluation, MRI, and tandem mass spectrometry were conducted to assess the patient's metabolic profile and neurological status. The pathogenic impact of the identified mutations (c.881G > A; p.Arg294Gln and c.481C > T; p.Arg161Trp) was analyzed using computational tools and molecular dynamics simulations. Molecular dynamics simulations indicated significant dynamic changes in the mutant protein structures. The R161W mutation increased flexibility, while the R294Q mutation caused notable conformational instability at the catalytic site, reducing its normal protein function and stability. The RMSD, RMSF, and SASA analyses supported these findings, correlating well with experimental observations. The molecular dynamics simulations provided valuable insights into the structural implications of the R161W and R294Q mutations and might contribute to a deeper understanding of GA1 molecular mechanisms.
Filiaciones:
Agrahari, AK:
Translat Hlth Sci & Technol Inst, NCR Biotech Sci Cluster, Faridabad, Haryana, India
Kuchay, RAH:
Baba Ghulam Shah Badshah Univ, Dept Biotechnol, Rajouri, J&K, India
Clemson Univ, Dept Phys & Astron, Clemson, SC 29634 USA
GMC, Dept Ophthalmol, Srinagar, J&K, India
UT Southwestern Med Ctr, Dept Radiol, Dallas, TX USA
Univ Nacl Autonoma Mexico, Inst Ophthalmol Conde Valenciana, Fac Med, Dept Biochem & Rare Dis Diagnost Unit, Mexico City, Mexico
Inst Ophthalmol Conde Valenciana, Mexico City, Mexico
IRCCS Ist Giannina Gaslini, Via Gerolamo Gaslini 5, I-16147 Genoa, Italy
NHO, Natl Inst Sensory Organs, Tokyo Med Ctr, Meguro, Japan
GMC, Dept Pediat, Srinagar, J&K, India
|