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Titolo:
MOLECULAR-BASIS OF AN ADULT FORM OF SANDHOFF DISEASE - SUBSTITUTION OF GLUTAMINE FOR ARGININE AT POSITION 505 OF THE BETA-CHAIN OF BETA-HEXOSAMINIDASE RESULTS IN A LABILE ENZYME
Autore:
BOLHUIS PA; PONNE NJ; BIKKER H; BAAS F; DEJONG JMBV;
Indirizzi:
UNIV AMSTERDAM,ACAD MED CTR,DEPT NEUROL 1105 AZ AMSTERDAM NETHERLANDS
Titolo Testata:
Biochimica et biophysica acta
fascicolo: 2, volume: 1182, anno: 1993,
pagine: 142 - 146
SICI:
0006-3002(1993)1182:2<142:MOAAFO>2.0.ZU;2-I
Fonte:
ISI
Lingua:
ENG
Soggetto:
HEXB GENE-MUTATIONS; AMINO-ACID-SEQUENCE; B DEFICIENCY; GM2 GANGLIOSIDOSIS; EXTENSIVE HOMOLOGY; LYSOSOMAL-ENZYME; 50-KB DELETION; ALPHA-SUBUNITS; CDNA; DNA;
Keywords:
HEXOSAMINIDASE; SANDHOFF DISEASE; GENETIC COMPOUND; AMINO ACID SUBSTITUTION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
35
Recensione:
Indirizzi per estratti:
Citazione:
P.A. Bolhuis et al., "MOLECULAR-BASIS OF AN ADULT FORM OF SANDHOFF DISEASE - SUBSTITUTION OF GLUTAMINE FOR ARGININE AT POSITION 505 OF THE BETA-CHAIN OF BETA-HEXOSAMINIDASE RESULTS IN A LABILE ENZYME", Biochimica et biophysica acta, 1182(2), 1993, pp. 142-146

Abstract

Sandhoff disease is a lysosomal storage disorder characterized by accumulation of G(M2) ganglioside due to mutations in the beta-chain of beta-hexosaminidase. Hexosaminidase activity is negligible in infantileSandhoff disease whereas residual activity is present in juvenile andadult forms. Here we report the molecular basis of the first described adult form of Sandhoff disease. Southern analysis of chromosomal DNAindicated the absence of chromosomal deletions in the gene encoding the beta-chain. Northern analysis of RNA from cultured fibroblasts demonstrated that at least one of the beta-chain alleles-was transcribed into normal-length mRNA. Sequence analysis of the entire cDNA prepared from poly-adenylated RNA showed that only one point mutation was present, consisting of a G --> A transition at nucleotide position 1514. This mutation changes the electric charge at amino acid position 505 by substitution of glutamine for arginine in a highly conserved part of the beta-chain, present even in the slime mold Dictyostelium discoideum. The nucleotide transition generated a new restriction site for DdeI,which was present in only one of the alleles of the patient. Reverse transcription of mRNA followed by restriction with DdeI resulted in complete digestion at the mutation site, demonstrating that the second allele was of an mRNA-negative type. Transfection of COS cells with a cDNA construct containing the mutation but otherwise the normal sequence resulted in the expression of a labile form of beta-hexosaminidase. These results show that the patient is a genetic compound, and that the lability of beta-hexosaminidase found in this form of Sandhoff disease is based on a single nucleotide transition.

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Documento generato il 01/12/20 alle ore 12:36:31