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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 Feb; 72(2):115-21.MG

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

Nakamura K
Department of Pediatrics, Gifu University School of Medicine, Gifu, Japan.
Fukao T
No affiliation info available
Perez-Cerda C
No affiliation info available
Luque C
No affiliation info available
Song XQ
No affiliation info available
Naiki Y
No affiliation info available
Kohno Y
No affiliation info available
Ugarte M
No affiliation info available
Kondo N
No affiliation info available

MeSH

Acetyl-CoA C-AcyltransferaseBinding SitesCysteineDNA Mutational AnalysisExonsFemaleFibroblastsGene DeletionHumansImmunoblottingIntronsMetabolism, Inborn ErrorsMitochondriaModels, GeneticMutationPoint MutationRNA Splice SitesRNA SplicingRNA, MessengerReverse Transcriptase Polymerase Chain ReactionTransfection

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., Kohno, Y., Ugarte, M., & 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), 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_ DB - PRIME DP - Unbound Medicine ER -
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