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A single origin for the most frequent mutation causing late infantile metachromatic leucodystrophy
J Zlotogora1, Y Furman-Shaharabani, A Harris
1Department of Human Genetics, Hadassah Hospital and Medical School, Hebrew University, Jerusalem, Israel.
Abstract:
Metachromatic leucodystrophy is an autosomal recessive degenerative disease of the nervous system caused by the deficiency of the lysosomal enzyme arylsulphatase A (ARSA). We report here on the high incidence of late infantile MLD among Muslim Arabs originating from Jerusalem, most probably because of a founder effect. All the patients were found to be homozygous for 459 + 1 G-->A, a mutation which destroys the splice donor site of exon 2 of the ARSA gene. This mutation has been reported to be the most common mutation causing MLD. We studied the ARSA haplotype defined by three intragenic polymorphic sites in DNA samples from Muslim Arab patients from Jerusalem, a Christian Arab patient originating from the region, and eight other white patients, all homozygous for the 459 + 1 G-->A mutation. All the alleles carried the same haplotype which is in complete linkage disequilibrium with the mutation. This finding indicates a common origin for the 459 + 1 G-->A mutation which may have been introduced into Jerusalem at the time of the Crusades.
Insights
Late infantile Metachromatic Leucodystrophy (MLD) is unusually common in Jerusalem
Area of Science:
- Genetics
- Neurology
- Biochemistry
Background:
- Metachromatic leucodystrophy (MLD) is a rare genetic disorder.
- It results from a deficiency in the arylsulphatase A (ARSA) enzyme.
- This deficiency leads to the degeneration of the nervous system.
Purpose of the Study:
- To investigate the high incidence of late infantile MLD in Muslim Arabs from Jerusalem.
- To identify the genetic cause and potential origin of this MLD cluster.
Main Methods:
- Genetic analysis of the ARSA gene in affected individuals.
- ARSA haplotype analysis using intragenic polymorphic sites.
- Comparison of haplotypes across different ethnic groups and geographical origins.
Main Results:
- A high frequency of late infantile MLD was observed in Muslim Arabs from Jerusalem.
- All patients were homozygous for the 459 + 1 G-->A mutation in the ARSA gene.
- A common ARSA haplotype was found in linkage disequilibrium with the mutation, suggesting a founder effect.
Conclusions:
- The 459 + 1 G-->A mutation in the ARSA gene is likely the cause of MLD in this population.
- A founder effect, possibly introduced during the Crusades, may explain the high incidence.
- This highlights the importance of genetic studies in understanding disease prevalence in specific populations.