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Updated: Feb 27, 2026
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Four novel ARSA gene mutations with pathogenic impacts on metachromatic leukodystrophy: a bioinformatics approach to
Masoumeh Dehghan Manshadi1, Behnam Kamalidehghan2,3, Omid Aryani1
1Department of Medical Genetics, Special Medical Center, Tehran, Iran.
Abstract:
Metachromatic leukodystrophy (MLD) disorder is a rare lysosomal storage disorder that leads to severe neurological symptoms and an early death. MLD occurs due to the deficiency of enzyme arylsulfatase A (ARSA) in leukocytes, and patients with MLD excrete sulfatide in their urine. In this study, the ARSA gene in 12 non-consanguineous MLD patients and 40 healthy individuals was examined using polymerase chain reaction sequencing. Furthermore, the structural and functional effects of new mutations on ARSA were analyzed using SIFT (sorting intolerant from tolerant), I-Mutant 2, and PolyPhen bioinformatics software. Here, 4 new pathogenic homozygous mutations c.585G>T, c.661T>A, c.849C>G, and c.911A>G were detected. The consequence of this study has extended the genotypic spectrum of MLD patients, paving way to a more effective method for carrier detection and genetic counseling.
Insights
Four new mutations in the arylsulfatase A (ARSA) gene were identified in Metachromatic leukodystrophy (MLD) patients. This research expands the known genetic variations for MLD, aiding carrier detection and genetic counseling.
Area of Science:
- Genetics
- Biochemistry
- Neurology
Background:
- Metachromatic leukodystrophy (MLD) is a rare, fatal lysosomal storage disorder.
- It is caused by arylsulfatase A (ARSA) enzyme deficiency, leading to neurological decline.
- Patients with MLD excrete sulfatide in their urine.
Purpose of the Study:
- To investigate the genetic basis of MLD in a cohort of patients.
- To identify novel mutations within the ARSA gene.
- To analyze the structural and functional impact of newly discovered mutations.
Main Methods:
- Polymerase chain reaction (PCR) sequencing of the ARSA gene in 12 MLD patients and 40 healthy controls.
- Bioinformatic analysis using SIFT, I-Mutant 2, and PolyPhen to predict mutation effects.
- Genotyping and functional impact assessment of identified mutations.
Main Results:
- Four novel pathogenic homozygous mutations (c.585G>T, c.661T>A, c.849C>G, and c.911A>G) in the ARSA gene were detected.
- These mutations were identified in non-consanguineous MLD patients.
- Bioinformatic tools predicted significant structural and functional consequences for these new mutations.
Conclusions:
- The study expands the known genotypic spectrum of Metachromatic leukodystrophy.
- Identification of new mutations provides a basis for improved carrier detection strategies.
- Findings support enhanced genetic counseling for families affected by MLD.
