Organization of the human liver carnitine palmitoyltransferase 1 gene ( CPT1A) and identification of novel mutations in hypoketotic hypoglycaemia.
Carnitine palmitoyltransferase 1A (CPT1A) deficiency is a rare autosomal recessive disorder of mitochondrial fatty acid oxidation. CPT1 controls the import of long-chain fatty acids into the mitochondria, where they are oxidized. Two CPT1 isoforms, the so-called "liver" and "muscle" CPT1s encoded by the CPT1Aand CPT1Bgenes, respectively, have been identified so far. While the cDNA sequences of both isoforms are known, only CPT1Bgene organization has yet been described. We took advantage of the working draft data to characterize the organization of the human CPT1A gene. We have shown the existence of 20 exons, spanning 60 kb of DNA. Two alternate promoters and numerous transcription factor-binding sites were identified within the 5' upstream region of the gene. In the 3' untranslated region, the major polyA signal was suggested to lie about 2 kb downstream of the stop codon. These data enabled us to characterize six novel mutations in four CPT1A-deficient patients; namely Q100X (exon 4), A414 V (exon 11), Y498C (exon 13), 1876-1G>A (intron 15), a 113-bp intronic insertion in the mature CPT1A mRNA (exon 13-14 junction), and a large 8-kb deletion encompassing intron 14 to exon 17. Thus, identification of the CPT1A gene organization contributes to improve the molecular screening in patients and provides tools for the study of the human CPT1A gene expression.
INSERM U393, Groupe Hospitalier Necker-Enfants Malades, Paris, France.
Stéphanie
S
Gobin
Jean-Paul
JP
Bonnefont
Carina
C
Prip-Buus
Claude
C
Mugnier
Magali
M
Ferrec
France
F
Demaugre
Jean-Marie
JM
Saudubray
Hidayeth
H
Rostane
Fatima
F
Djouadi
William
W
Wilcox
Stephen
S
Cederbaum
Richard
R
Haas
William L
WL
Nyhan
Anne
A
Green
George
G
Gray
Jean
J
Girard
Laure
L
Thuillier
D015152:Blotting, Northern; D002334:Carnitine O-Palmitoyltransferase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D016883:Diabetic Ketoacidosis / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005347:Fibroblasts / Q000502:physiology; D017353:Gene Deletion; D006801:Humans; D007003:Hypoglycemia / Q000201:enzymology / Q000235:genetics*; D007438:Introns / Q000235:genetics; D008099:Liver / Q000201:enzymology*; D008214:Lymphocytes / Q000502:physiology; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000502:physiology; D020506:Untranslated Regions / Q000235:genetics
D017931:DNA Primers; D012333:RNA, Messenger; D020506:Untranslated Regions; D002334:Carnitine O-Palmitoyltransferase