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Titolo:
Two mutations remote from an exon/intron junction in the beta-hexosaminidase beta-subunit gene affect 3 '-splice site selection and cause Sandhoff disease
Autore:
Fujimaru, M; Tanaka, A; Choeh, K; Wakamatsu, N; Sakuraba, H; Isshiki, G;
Indirizzi:
Osaka City Univ, Sch Med, Dept Pediat, Abeno Ku, Osaka 5458585, Japan Osaka City Univ Osaka Japan 5458585 diat, Abeno Ku, Osaka 5458585, Japan Eulji Med Coll Hosp, Dept Pediat, Taejon, South Korea Eulji Med Coll HospTaejon South Korea Dept Pediat, Taejon, South Korea Univ Tokushima, Sch Med, Dept Internal Med 1, Tokushima 770, Japan Univ Tokushima Tokushima Japan 770 Internal Med 1, Tokushima 770, Japan Tokyo Metropolitan Inst Med Sci, Dept Clin Genet, Tokyo 113, Japan Tokyo Metropolitan Inst Med Sci Tokyo Japan 113 Genet, Tokyo 113, Japan
Titolo Testata:
HUMAN GENETICS
fascicolo: 4, volume: 103, anno: 1998,
pagine: 462 - 469
SICI:
0340-6717(199810)103:4<462:TMRFAE>2.0.ZU;2-Z
Fonte:
ISI
Lingua:
ENG
Soggetto:
RNA SPLICING INVITRO; MESSENGER-RNA; BRANCHPOINT SEQUENCE; EXON MUTATION; ALPHA-GENE; HEXB GENE; INTRON; IDENTIFICATION; TRANSCRIPTS; ENHANCERS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
28
Recensione:
Indirizzi per estratti:
Indirizzo: Tanaka, A Osaka458585,niv, Sch Med, Dept Pediat, Abeno Ku, 1-4-3 Asahi Machi, Osaka 5 Osaka City Univ 1-4-3 Asahi Machi Osaka Japan 5458585 , Osaka 5
Citazione:
M. Fujimaru et al., "Two mutations remote from an exon/intron junction in the beta-hexosaminidase beta-subunit gene affect 3 '-splice site selection and cause Sandhoff disease", HUM GENET, 103(4), 1998, pp. 462-469

Abstract

Four unrelated Japanese patients with infantile Sandhoff disease (beta-hexosaminidase beta-subunit deficiency) have been studied for the molecular basis of their severe phenotype. Two patients had complex base substitutions;one patient was homoallelic for a triple mutation (P417L, K121R, and S255R) and the other was a compound heterozygote of a double (P417L and K121R) mutation and the triple mutation. K121R is known to be a functional polymorphism, while P417L (exon Il, +8 C-->T)generates predominantly an abnormally spliced mRNA at base +112 of exon II and has been described in two patientswith a juvenile form of the disease. The mild phenotype is attributed to the presence of a small amount of normally spliced mRNA. S255R is a novel mutation without prior description in the literature. An expression study of the normally spliced cDNA with the double and the triple mutations gave about 70% and 30% of normal activity, respectively. This finding suggests thatS255R further reduces the catalytic activity of the already below-threshold amount of normally spliced mRNA and accounts for the more severe phenotype in our patients. In the other two patients, a novel disease-causing base transition was found within intron 10, away from the intron/exon junction (-17 a-->g). This mutation caused abnormal 3' splicing at position -37 of intron 10, and no normally spliced product was detectable upon RT-P(SR analysis. We noted an unusually low splice site score (61.8) for the exon 10/intron Il junction and suspected that this might be partially responsible for the aberrant splicing in these mutations. To test this hypothesis, we constructed four chimeric cDNAs all with an additional intron 10 inserted and evaluated their splicing efficiency. They, respectively, had the normal sequence, P417L (exon 11, +8 C-->T), the intronic mutation (-17 a-->g), and the intronic mutation with an artificially engineered intron 10/exon 11 junctionof a higher splice site score (85.1). Of the total transcripts, 67% and 32% were correctly spliced in the normal chimeric construct and P417L, respectively, while no normally spliced product was generated either in the chimeric construct with -17 a-->g or in that with a high splice site score. The sequence around the adenosine -17 residue upstream of the normal acceptor splice site in this report, UGCAAU (-21 to -16), matches the consensus branchpoint sequence YNYRAY (Y, pyrimidine; R, purine; N, any base) reported in the literature. The mutation in this study is most likely to abolish lariatformation because the artificial site of the high splice site score did not improve splicing efficiency.

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Documento generato il 21/09/20 alle ore 17:43:43