Clinical, Molecular, and Computational Analysis Showed a Novel Homozygous Mutation Among the Substrate-Binding Site of ARSA Protein in Consanguineous Family with Late-Infantile MLD

• DOI: 10.1007/s12031-018-1141-z
• Publication Date: 2018-08-06T08:01:21Z
• Authors: Abir Ben Issa; Fatma Kammoun Feki; Marwa Ben Jdila; Boudour Khabou; Bochra Ben Rhouma; Leila Ammar-Keskes; Chahnez Triki; Faiza Fakhfakh
• Keywords: Male; Heterozygote; 0303 health sciences; Binding Sites; Homozygote; Mutation, Missense; Infant; Exons; Leukodystrophy, Metachromatic; Molecular Dynamics Simulation; Pedigree; 3. Good health; Consanguinity; 03 medical and health sciences; Child, Preschool; Humans; Female; Cerebroside-Sulfatase; Protein Binding

Metachromatic leukodystrophy (MLD) is a neurodegenerative disorder characterized by progressive demyelination resulting from impaired degradation and thus the accumulation of cerebroside-3-sulfate (sulfatide). It is caused by the deficiency of arylsulfatase A (ARSA) enzyme which is encoded by the ARSA gene. The present study reports the clinical, molecular, and bioinformatic investigation of three patients belonging to a consanguineous family with late-infantile MLD disorder. The results revealed a novel homozygous missense mutation c.699C>A (p.His231Gln) in exon 4 of ARSA gene in the three patients inherited from their heterozygous parents. Interestingly, this novel mutation is the second mutation identified in the substrate-binding site of ARSA protein and it was classified as damaging and deleterious by several bioinformatics tools. The c.699C>A (p.His231Gln) leads to changes in the pre-mRNA secondary structure and in the ARSA protein 3D structure with a significant root mean square deviation value which could probably affect its stability and function.