MOLECULAR-BASIS OF LATE INFANTILE METACHROMATIC LEUKODYSTROPHY IN THEHABBANITE JEWS

Late infantile metachromatic leukodystrophy (MLD) is a neurodegenerati ve disease, most commonly caused by the deficiency of the lysosomal en zyme arylsulfatase A (ARSA). Late infantile MLD is frequent (1/75 live birth) in a small Jewish community which lived in Habban, isolated fr om the other Jewish populations. The gene coding for ARSA was sequence d in one of the Habbanite patients, who was found to be homozygous for an allele having three mutations. Two mutations are A to G transition s 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 characteristic for the ARSA pseudodefi ciency (PD) alle le, which in homozygozity is associated with low enzymatic activity, b ut does not cause disease. The third mutation, which occurred on the b ackground of the PD allele, is a C to T transition at position 2119, p redicting a substitution of proline-377 by leucine (P377L). Biosynthes is studies performed with cells expressing the ARSA cDNA into which th is mutation was introduced demon strated 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 obs ervations confirm the genealogical data which pointed to a common ance stor for all the carriers of MLD among the Habbanite Jews, In addition , the same mutation was demonstrated to be relatively frequent among t he Yemenite Jews. The origin and the means by which the mutation sprea d between the two communities remain unknown. (C) 1995 Wiley-Liss, Inc .