Publication

Rationale for a conditional knockout mouse model to study carnitine palmitoyltransferase I deficiencies

van der Leij, FR., Drijfholt, A. & Kuipers, JRG., 1999, CURRENT VIEWS OF FATTY ACID OXIDATION AND KETOGENESIS. Quant, PA. & Eaton, S. (eds.). NEW YORK: Kluwer Academic/Plenum Publishers, p. 377-385 9 p. (ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY; vol. 466).

Research output: Chapter in Book/Report/Conference proceedingConference contributionAcademicpeer-review

  • FR van der Leij
  • A Drijfholt
  • JRG Kuipers

Several severe congenital cardiomyopathies are known to be associated with deficiencies in long-chain fatty acid transport and oxidation. Our studies are focused on a key enzyme in the regulation of intracellular long-chain fatty acid transport: carnitine palmitoyltransferase 1. Of this enzyme, two isoforms are expressed in the neonatal heart: L-CPT1 (the "liver-type" isoform) and M-CPT1 (the "muscle-type" isoform). It is known from studies in rats that chemical inhibition of both CPT1 isoforms results in hypertrophy of the cardiomyocytes, leading to an increase in heart-weight of up to 25%. With the aid of expressed sequence tag database analyses, cDNA- and genomic sequence information, we analysed the human gene for M-CPT1 in detail, and obtained partial clones of the murine genes for both CPT1 isoforms. We now started the development of a conditional knockout model to analyse and dissect deficiencies in these genes. While of the other mitochondrial components of the carnitine system deficiencies are known, some with severe cardiac consequences, M-CPT1 deficiencies have never been described. This suggests that M-CPT1 deficiency either(1) has not been recognised within the pool of congenital disorders, (2) is detrimental in an early stage of reproduction or embryogenesis, or (3) does not lead to physiological problems, probably due to the existence of a rescue system. If (1) is the case, the phenotypic effects of M-CPT1 deficiency have to be studied in order to generate criteria for clinical decision making and diagnosis. Option (2) demonstrates the necessity to use novel vector systems to create conditional gene disruptions. Hypothesis (3) implies a possible role for L-CPT1, and a knockout model allows a study of the interaction between the genes for L-CPT1 and M-CPT1. Applicable strategies to develop such a model system will be discussed.

Original languageEnglish
Title of host publicationCURRENT VIEWS OF FATTY ACID OXIDATION AND KETOGENESIS
EditorsPA Quant, S Eaton
Place of PublicationNEW YORK
PublisherKluwer Academic/Plenum Publishers
Pages377-385
Number of pages9
ISBN (Print)0-306-46200-1
Publication statusPublished - 1999
Event4th Fatty Acid Oxidation and Ketogenesis Conference - London
Duration: 3-Apr-19986-Apr-1998

Publication series

NameADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY
PublisherKLUWER ACADEMIC / PLENUM PUBL
Volume466
ISSN (Print)0065-2598

Conference

Conference4th Fatty Acid Oxidation and Ketogenesis Conference
CityLondon
Period03/04/199806/04/1998

Event

4th Fatty Acid Oxidation and Ketogenesis Conference

03/04/199806/04/1998

London

Event: Conference

    Keywords

  • ACYLCARNITINE TRANSLOCASE DEFICIENCY, PALMITOYL TRANSFERASE DEFICIENCY, CRE RECOMBINASE, DNA RECOMBINATION, HUMAN LIVER, RAT-HEART, CPT-I, GENE, CELLS, EXPRESSION

ID: 3853495