Identification and structural characterization of a pathogenic ARSA missense variant in two consanguineous families from Jammu and Kashmir (India) with late infantile metachromatic leukodystrophy

• Published in: Molecular biology reports 2024-12, Vol.51 (1), p.30-30, Article 30
• Main Authors: Mir, Yaser Rafiq, Agrahari, Ashish Kumar, Hassan, Asima, Choudhary, Abhishek, Asthana, Shailendra, Taneja, Atul Kumar, Nawaz, Shah, Ilyas, Mohd, Scotti, Claudia, Kuchay, Raja A. H.
• Format: Article
• Language: English
• Subjects: Animal Anatomy; Animal Biochemistry; ARSA protein; Arylsulfatase; Biochemical analysis; Biomedical and Life Sciences; Cerebroside-sulfatase; Cerebroside-Sulfatase - genetics; Cognitive ability; Consanguinity; Enzymatic activity; Esterases; Genetic analysis; Histology; Humans; India; Leukodystrophy; Leukodystrophy, Metachromatic - diagnostic imaging; Leukodystrophy, Metachromatic - genetics; Life Sciences; Molecular Dynamics Simulation; Molecular modelling; Morphology; Mutation; Original Article; Pathogenicity
• ISSN: 0301-4851; 1573-4978
• DOI: 10.1007/s11033-023-09072-2

Background Metachromatic leukodystrophy (MLD) is a rare lysosomal storage disorder caused by a deficiency of Arylsulfatase A (ARSA) enzyme activity. Its clinical manifestations include progressive motor and cognitive decline. ARSA gene mutations are frequent in MLD. Methods and results In the present study, whole exome sequencing (WES) was employed to decipher the genetic cause of motor and cognitive decline in proband’s of two consanguineous families from J&K (India). Clinical investigations using radiological and biochemical analysis revealed MLD-like features. WES confirmed a pathogenic variant in the ARSA gene. Molecular simulation dynamics was applied for structural characterization of the variant. Conclusion We report the identification of a pathogenic missense variant (c.1174 C > T; p.Arg390Trp) in the ARSA gene in two cases of late infantile MLD from consanguineous families in Jammu and Kashmir, India. Our study utilized genetic analysis and molecular dynamics simulations to identify and investigate the structural consequences of this mutation. The molecular dynamics simulations revealed significant alterations in the structural dynamics, residue interactions, and stability of the ARSA protein harbouring the p.Arg390Trp mutation. These findings provide valuable insights into the molecular mechanisms underlying the pathogenicity of this variant in MLD.