A novel single-base substitution (c.1124A>G) that activates a 5-base upstream cryptic splice donor site within exon 11 in the human mitochondrial acetoacetyl-CoA thiolase gene

被引：15

作者：

Fukao, Toshiyuki ^{[1
,2
]}

Boneh, Avihu ^{[3
]}

Aoki, Yusuke ^{[1
]}

Kondo, Naomi ^{[1
]}

机构：

[1] Gifu Univ, Grad Sch Med, Dept Pediat, Gifu 5011194, Japan

[2] Gifu Univ, United Grad Sch Drug Discovery & Med Informat Sci, Div Med Informat Sci, Gifu 5011194, Japan

[3] Univ Melbourne, Royal Childrens Hosp, Dept Paediat, Murdoch Childrens Res Inst,Metab Serv, Melbourne, Vic 3010, Australia

来源：

MOLECULAR GENETICS AND METABOLISM | 2008年 / 94卷 / 04期

关键词：

aberrant splicing; exonic mutation; splice site selection; mitochondrial acetoacetyl-CoA thiolase; inborn error of metabolism;

D O I：

10.1016/j.ymgme.2008.04.014

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Most mutations related to aberrant splicing occur in conserved splice acceptor and donor sites. Some exonic mutations also affect splicing. We identified and characterized a point mutation (c.1124A>G) in an Australian patient (GK43) with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. GK43 is a homozygote of c.1124A>G, which activates a cryptic splice donor site 5 bases upstream from c.1124A>G within exon 11, causing aberrant splicing in most transcripts. The aberrant splicing results in c.1120-1163 (44-base) deletion, causing a frameshift in T2 mRNA. A mini-gene splicing experiment confirmed that the c.1124A>G substitution was responsible for this aberrant splicing. This cryptic splice site has a Shapiro and Senapathy score (70.0) in a normal sequence but if mutated, the score (84.3) becomes higher than the one in the authentic splice donor site of intron 11 (81.4). This is an example in which a point mutation activates a cryptic splice donor site motif that is used preferentially over a downstream authentic splice site. (C) 2008 Elsevier Inc. All rights reserved.

引用

页码：417 / 421

页数：5

共 39 条

[1] Factor VII gene intronic mutation in a lethal factor VII deficiency:: effects on splice-site selection [J].

Borensztajn, K ;

Sobrier, ML ;

Fischer, AM ;

Chafa, O ;

Amselem, S ;

Tapon-Bretaudière, J .

BLOOD, 2003, 102 (02) :561-563

[2] Oriented scanning is the leading mechanism underlying 5′ splice site selection in mammals [J].

Borensztajn, Keren ;

Sobrier, Marie-Laure ;

Duquesnoy, Philippe ;

Fischer, Anne-Marie ;

Tapon-Bretaudiere, Jacqueline ;

Amselem, Serge .

PLOS GENETICS, 2006, 2 (09) :1297-1306

[3] Aberrant 5′ splice sites in human disease genes:: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization [J].

Buratti, Emanuele ;

Chivers, Martin ;

Kralovicova, Jana ;

Romano, Maurizio ;

Baralle, Marco ;

Krainer, Adrian R. ;

Vorechovsky, Igor .

NUCLEIC ACIDS RESEARCH, 2007, 35 (13) :4250-4263

[4]

DAUM RS, 1971, LANCET, V2, P1289

[5]

Fukao T, 1997, HUM MUTAT, V9, P277, DOI 10.1002/(SICI)1098-1004(1997)9:3<277::AID-HUMU11>3.3.CO

[6]

2-T

[7] MITOCHONDRIAL ACETOACETYL COENZYME-A THIOLASE GENE - A NOVEL 68-BP DELETION INVOLVING 3' SPLICE-SITE OF INTRON-7, CAUSING EXON-8 SKIPPING IN A CAUCASIAN PATIENT WITH BETA-KETOTHIOLASE DEFICIENCY [J].

FUKAO, T ;

SONG, XQ ;

YAMAGUCHI, S ;

ORII, T ;

WANDERS, RJA ;

POLLTHE, BT ;

HASHIMOTO, T .

HUMAN MUTATION, 1995, 5 (01) :94-96

[8] MOLECULAR-CLONING AND SEQUENCE OF THE COMPLEMENTARY-DNA ENCODING HUMAN MITOCHONDRIAL ACETOACETYL-COENZYME-A THIOLASE AND STUDY OF THE VARIANT ENZYMES IN CULTURED FIBROBLASTS FROM PATIENTS WITH 3-KETOTHIOLASE DEFICIENCY [J].

FUKAO, T ;

YAMAGUCHI, S ;

KANO, M ;

ORII, T ;

FUJIKI, Y ;

OSUMI, T ;

HASHIMOTO, T .

JOURNAL OF CLINICAL INVESTIGATION, 1990, 86 (06) :2086-2092

[9] MOLECULAR-BASIS OF BETA-KETOTHIOLASE DEFICIENCY - MUTATIONS AND POLYMORPHISMS IN THE HUMAN MITOCHONDRIAL ACETOACETYL-COENZYME-A THIOLASE GENE [J].

FUKAO, T ;

YAMAGUCHI, S ;

ORII, T ;

HASHIMOTO, T .

HUMAN MUTATION, 1995, 5 (02) :113-120

[10] Enzymes of ketone body utilization in human tissues: Protein and messenger RNA levels of succinyl-coenzyme A (CoA):3-ketoacid CoA transferase and mitochondrial and cytosolic acetoacetyl-CoA thiolases [J].

Fukao, T ;

Song, XQ ;

Mitchell, GA ;

Yamaguchi, S ;

Sukegawa, K ;

Orii, T ;

Kondo, N .

PEDIATRIC RESEARCH, 1997, 42 (04) :498-502

← 1 2 3 4 →

A novel single-base substitution (c.1124A&gt;G) that activates a 5-base upstream cryptic splice donor site within exon 11 in the human mitochondrial acetoacetyl-CoA thiolase gene

A novel single-base substitution (c.1124A>G) that activates a 5-base upstream cryptic splice donor site within exon 11 in the human mitochondrial acetoacetyl-CoA thiolase gene