Molecular basis of late infantile metachromatic leukodystrophy in the Habbanite Jews.

Late infantile metachromatic leukodystrophy (MLD) is a neurodegenerative disease, most commonly caused by the deficiency of the lysosomal enzyme arylsulfatase A (ARSA). Late infantile MLD is frequent (1/75 live birth) in a small Jewish community which lived in Habban, isolated from the other Jewish populations. The gene coding for ARSA was sequenced in one of the Habbanite patients, who was found to be homozygous for an allele having three mutations. Two mutations are A to G transitions in the ARSA gene at positions 1788 and 2723, causing the loss of an N-glycosylation site and a polyadenylation signal, respectively. These mutations are characteristics for the ARSA pseudodeficiency (PD) allele, which in homozygozity is associated with low enzymatic activity, but does not cause disease. The third mutation, which occurred on the background of the PD allele, is a C to T transition at position 2119, predicting a substitution of proline-377 by leucine (P377L). Biosynthesis studies performed with cells expressing the ARSA cDNA into which this mutation was introduced demonstrated a severely reduced half-life of the mutant enzyme. Five of 10 patients from the Habbanite community could be studied and were homozygous for the P377L allele. These observations confirm the genealogical data which pointed to a common ancestor for all the carriers of MLD among the Habbanite Jews. In addition, the same mutation was demonstrated to be relatively frequent among the Yemenite Jews. The origin and the means by which the mutation spread between the two communities remain unknown.