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J Neurol Sci. 2002 Mar 30;195(2):129-38.

Compound heterozygosity with two novel mutations in the HEXB gene produces adult Sandhoff disease presenting as a motor neuron disease phenotype.

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1
Department of Neurology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, 305-8575, Tsukuba, Japan. toshi-yo@md.tsukuba.ac.jp

Abstract

Little information is available on molecular defects involved in adult Sandhoff disease presenting as motor neuron disease phenotype. We studied enzyme activities of beta-hexosaminidase (Hex) and the HEXB gene encoding the beta-subunit of Hex in a family of the Japanese case. Enzyme assay with 4-methylumbelliferyl-2-acetamido-2-deoxy-beta-D-glucopyranoside revealed a reduction in Hex A and B activity in proband's leukocytes. Although the activity of both in the mother were intermediate between those of controls and the proband, only Hex B reduction determined with heat inactivation was found in the father. Analysis of HEXB gene demonstrated two novel point mutations. The first mutation, IVS2-1G>A, was located at the 3'-splice acceptor site of intron 2 derived from the mother, causing exon 3 skipping. The resultant mRNA encoded a shorter beta-chain, which may not form an active enzyme. The second mutation was a G-to-A transition in exon 13 (c.1598G>A) derived from the father and resulted in arginine-to-histidine substitution at amino acid position 533 (R533H). Expression of R533H mutation in COS-1 cells demonstrated a lack of normal Hex activity, indicating that this mutation is pathological. Compound heterozygosity of these two mutations may trigger the development of adult Sandhoff disease with a motor neuron disease phenotype.

PMID:
11897243
[Indexed for MEDLINE]

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