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A novel single-base substitution (380C>T) that activates a 5-base downstream cryptic splice-acceptor site within exon 5 in almost all transcripts in the human mitochondrial acetoacetyl-CoA thiolase gene.
Mol Genet Metab 2001; 72(2):115-21MG

Abstract

Most mutation-related aberrant splicing occurs in the conserved splice-acceptor and -donor sites and some exonic mutations also affect splicing. We identified and characterized a point mutation (380C>T) in a Spanish patient (GK25) with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. GK25 is a homozygote of 380C>T, which activates a cryptic splice-acceptor site 5 bases downstream from 380C>T within exon 5, causing aberrant splicing in 94% of transcripts. The aberrant splicing results in a 17-amino acids deletion, including the active-site 126Cys. The 380C>T mutation also results in A127V mutation in 6% of transcripts. Transient expression analysis showed that the A127V mutation did not retain T2 activity, indicating that 380C>T was a null mutation. Although this cryptic splice site has a higher Shapiro and Senapathy's score (86) in even a normal sequence than the authentic splice-acceptor site of intron 4 (78), it is not used in normal controls. While the 380C>T mutation increases the score slightly (90), the cryptic splice site is used in almost all transcripts in GK25 fibroblasts. This is an example in which a point mutation activates a cryptic splice-acceptor site motif that is used preferentially over the upstream authentic splice site.

Authors+Show Affiliations

Department of Pediatrics, Gifu University School of Medicine, Gifu, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11161837

Citation

Nakamura, K, et al. "A Novel Single-base Substitution (380C>T) That Activates a 5-base Downstream Cryptic Splice-acceptor Site Within Exon 5 in Almost All Transcripts in the Human Mitochondrial acetoacetyl-CoA Thiolase Gene." Molecular Genetics and Metabolism, vol. 72, no. 2, 2001, pp. 115-21.
Nakamura K, Fukao T, Perez-Cerda C, et al. A novel single-base substitution (380C>T) that activates a 5-base downstream cryptic splice-acceptor site within exon 5 in almost all transcripts in the human mitochondrial acetoacetyl-CoA thiolase gene. Mol Genet Metab. 2001;72(2):115-21.
Nakamura, K., Fukao, T., Perez-Cerda, C., Luque, C., Song, X. Q., Naiki, Y., ... Kondo, N. (2001). A novel single-base substitution (380C>T) that activates a 5-base downstream cryptic splice-acceptor site within exon 5 in almost all transcripts in the human mitochondrial acetoacetyl-CoA thiolase gene. Molecular Genetics and Metabolism, 72(2), pp. 115-21.
Nakamura K, et al. A Novel Single-base Substitution (380C>T) That Activates a 5-base Downstream Cryptic Splice-acceptor Site Within Exon 5 in Almost All Transcripts in the Human Mitochondrial acetoacetyl-CoA Thiolase Gene. Mol Genet Metab. 2001;72(2):115-21. PubMed PMID: 11161837.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel single-base substitution (380C>T) that activates a 5-base downstream cryptic splice-acceptor site within exon 5 in almost all transcripts in the human mitochondrial acetoacetyl-CoA thiolase gene. AU - Nakamura,K, AU - Fukao,T, AU - Perez-Cerda,C, AU - Luque,C, AU - Song,X Q, AU - Naiki,Y, AU - Kohno,Y, AU - Ugarte,M, AU - Kondo,N, PY - 2001/2/13/pubmed PY - 2001/5/1/medline PY - 2001/2/13/entrez SP - 115 EP - 21 JF - Molecular genetics and metabolism JO - Mol. Genet. Metab. VL - 72 IS - 2 N2 - Most mutation-related aberrant splicing occurs in the conserved splice-acceptor and -donor sites and some exonic mutations also affect splicing. We identified and characterized a point mutation (380C>T) in a Spanish patient (GK25) with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. GK25 is a homozygote of 380C>T, which activates a cryptic splice-acceptor site 5 bases downstream from 380C>T within exon 5, causing aberrant splicing in 94% of transcripts. The aberrant splicing results in a 17-amino acids deletion, including the active-site 126Cys. The 380C>T mutation also results in A127V mutation in 6% of transcripts. Transient expression analysis showed that the A127V mutation did not retain T2 activity, indicating that 380C>T was a null mutation. Although this cryptic splice site has a higher Shapiro and Senapathy's score (86) in even a normal sequence than the authentic splice-acceptor site of intron 4 (78), it is not used in normal controls. While the 380C>T mutation increases the score slightly (90), the cryptic splice site is used in almost all transcripts in GK25 fibroblasts. This is an example in which a point mutation activates a cryptic splice-acceptor site motif that is used preferentially over the upstream authentic splice site. SN - 1096-7192 UR - https://www.unboundmedicine.com/medline/citation/11161837/A_novel_single_base_substitution__380C>T__that_activates_a_5_base_downstream_cryptic_splice_acceptor_site_within_exon_5_in_almost_all_transcripts_in_the_human_mitochondrial_acetoacetyl_CoA_thiolase_gene_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1096-7192(00)93125-1 DB - PRIME DP - Unbound Medicine ER -