title: Compound heterozygosity with two novel mutations in the HEXB gene produces adult Sandhoff disease presenting as a motor neuron disease phenotype.
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.
authors.affiliation: Department of Neurology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, 305-8575, Tsukuba, Japan. toshi-yo@md.tsukuba.ac.jp
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Yoshizawa
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kohno
authors.forename: Sumiko
authors.initials: S
authors.lastname: Nissato
authors.forename: Shin'ichi
authors.initials: S
authors.lastname: Shoji
mesh_terms: D000328:Adult; D017398:Alternative Splicing / Q000235:genetics; D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D019556:COS Cells; D002490:Central Nervous System / Q000201:enzymology* / Q000503:physiopathology; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology; D006579:Heterozygote; D054818:Hexosaminidase A; D054819:Hexosaminidase B; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D016472:Motor Neuron Disease / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D012497:Sandhoff Disease / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D012737:Sex Factors; D014162:Transfection; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics* / Q000378:metabolism
chemical_list: D054818:Hexosaminidase A; D054819:Hexosaminidase B; D001619:beta-N-Acetylhexosaminidases