Abstract
The enzyme carnitine-acylcarnitine translocase (CACT) is involved in the transport of long-chain fatty acids into mitochondria. CACT deficiency is a life-threatening, recessively inherited disorder of lipid β-oxidation which manifests in early infancy with hypoketotic hypoglycemia, cardiomyopathy, liver failure, and muscle weakness. We report here the clinical, biochemical, and molecular features of six CACT-deficient patients from Italy, Spain, and North America who exhibited significant clinical heterogeneity. In five patients (Patients 1, 2, 4, 5, and 6) the disease manifested in the neonatal period, while the remaining patient (Patient 3), the younger sibling of an infant who had died with clinical suspicion of fatty acid oxidation defect, has been treated since birth and was clinically asymptomatic at 4.5 years of age. Patients 1 and 4 were deceased within 6 months from the onset of this study, while the remaining four are still alive at 8, 4.5, 3.5, and 2 years, respectively. Sequence analysis of the CACT gene (SLC25A20) disclosed five novel mutations and three previously reported mutations. Three patients were homozygous for the identified mutations. Two of the novel mutations (c.718 + 1G > C and c.843 + 4_843 + 50del) altered the donor splice site of introns 7 and 8, respectively. The 47-nt deletion in intron 8 caused both skipping of exon 8 only and skipping of exons 6-8. Four mutations {[c.159dupT;c.163delA] ([p.Gly54Trp;p.Thr55Ala]) c.397C > T (p.Arg133Trp), c.691G > C (p.Asp231His), and c.842C > T (p.Ala281Val)} resulted in amino acid substitutions affecting evolutionarily conserved regions of the protein. Interestingly, one of these exonic mutations (p.Ala281Val) was associated with a splicing defect also characterized by skipping of exons 6-8. The deleterious effect of the p.Arg133Trp substitution was demonstrated by measuring CACT activity upon expression of the normal and the mutant protein in E. coli and functional reconstitution into liposomes. Combined analysis of clinical, biochemical, and molecular data failed to indicate a correlation between the phenotype and the genotype.
| Original language | English |
|---|---|
| Pages (from-to) | 312-320 |
| Number of pages | 9 |
| Journal | Human Mutation |
| Volume | 24 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2004 |
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Keywords
- Cardiomyopathy
- Fatty acids
- Metabolic disease
- Mitochondria
- Mutation analysis
- SLC25A20
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
Molecular and functional analysis of SLC25A20 mutations causing carnitine-acylcarnitine translocase deficiency. / Iacobazzi, Vito; Invernizzi, Federica; Baratta, Silvia; Pons, Roser; Chung, Wendy; Garavaglia, Barbara; Dionisi-Vici, Carlo; Ribes, Antonia; Parini, Rossella; Huertas, Maria Dolores; Roldan, Susana; Lauria, Graziantonio; Palmieri, Ferdinando; Taroni, Franco.
In: Human Mutation, Vol. 24, No. 4, 2004, p. 312-320.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Molecular and functional analysis of SLC25A20 mutations causing carnitine-acylcarnitine translocase deficiency
AU - Iacobazzi, Vito
AU - Invernizzi, Federica
AU - Baratta, Silvia
AU - Pons, Roser
AU - Chung, Wendy
AU - Garavaglia, Barbara
AU - Dionisi-Vici, Carlo
AU - Ribes, Antonia
AU - Parini, Rossella
AU - Huertas, Maria Dolores
AU - Roldan, Susana
AU - Lauria, Graziantonio
AU - Palmieri, Ferdinando
AU - Taroni, Franco
PY - 2004
Y1 - 2004
N2 - The enzyme carnitine-acylcarnitine translocase (CACT) is involved in the transport of long-chain fatty acids into mitochondria. CACT deficiency is a life-threatening, recessively inherited disorder of lipid β-oxidation which manifests in early infancy with hypoketotic hypoglycemia, cardiomyopathy, liver failure, and muscle weakness. We report here the clinical, biochemical, and molecular features of six CACT-deficient patients from Italy, Spain, and North America who exhibited significant clinical heterogeneity. In five patients (Patients 1, 2, 4, 5, and 6) the disease manifested in the neonatal period, while the remaining patient (Patient 3), the younger sibling of an infant who had died with clinical suspicion of fatty acid oxidation defect, has been treated since birth and was clinically asymptomatic at 4.5 years of age. Patients 1 and 4 were deceased within 6 months from the onset of this study, while the remaining four are still alive at 8, 4.5, 3.5, and 2 years, respectively. Sequence analysis of the CACT gene (SLC25A20) disclosed five novel mutations and three previously reported mutations. Three patients were homozygous for the identified mutations. Two of the novel mutations (c.718 + 1G > C and c.843 + 4_843 + 50del) altered the donor splice site of introns 7 and 8, respectively. The 47-nt deletion in intron 8 caused both skipping of exon 8 only and skipping of exons 6-8. Four mutations {[c.159dupT;c.163delA] ([p.Gly54Trp;p.Thr55Ala]) c.397C > T (p.Arg133Trp), c.691G > C (p.Asp231His), and c.842C > T (p.Ala281Val)} resulted in amino acid substitutions affecting evolutionarily conserved regions of the protein. Interestingly, one of these exonic mutations (p.Ala281Val) was associated with a splicing defect also characterized by skipping of exons 6-8. The deleterious effect of the p.Arg133Trp substitution was demonstrated by measuring CACT activity upon expression of the normal and the mutant protein in E. coli and functional reconstitution into liposomes. Combined analysis of clinical, biochemical, and molecular data failed to indicate a correlation between the phenotype and the genotype.
AB - The enzyme carnitine-acylcarnitine translocase (CACT) is involved in the transport of long-chain fatty acids into mitochondria. CACT deficiency is a life-threatening, recessively inherited disorder of lipid β-oxidation which manifests in early infancy with hypoketotic hypoglycemia, cardiomyopathy, liver failure, and muscle weakness. We report here the clinical, biochemical, and molecular features of six CACT-deficient patients from Italy, Spain, and North America who exhibited significant clinical heterogeneity. In five patients (Patients 1, 2, 4, 5, and 6) the disease manifested in the neonatal period, while the remaining patient (Patient 3), the younger sibling of an infant who had died with clinical suspicion of fatty acid oxidation defect, has been treated since birth and was clinically asymptomatic at 4.5 years of age. Patients 1 and 4 were deceased within 6 months from the onset of this study, while the remaining four are still alive at 8, 4.5, 3.5, and 2 years, respectively. Sequence analysis of the CACT gene (SLC25A20) disclosed five novel mutations and three previously reported mutations. Three patients were homozygous for the identified mutations. Two of the novel mutations (c.718 + 1G > C and c.843 + 4_843 + 50del) altered the donor splice site of introns 7 and 8, respectively. The 47-nt deletion in intron 8 caused both skipping of exon 8 only and skipping of exons 6-8. Four mutations {[c.159dupT;c.163delA] ([p.Gly54Trp;p.Thr55Ala]) c.397C > T (p.Arg133Trp), c.691G > C (p.Asp231His), and c.842C > T (p.Ala281Val)} resulted in amino acid substitutions affecting evolutionarily conserved regions of the protein. Interestingly, one of these exonic mutations (p.Ala281Val) was associated with a splicing defect also characterized by skipping of exons 6-8. The deleterious effect of the p.Arg133Trp substitution was demonstrated by measuring CACT activity upon expression of the normal and the mutant protein in E. coli and functional reconstitution into liposomes. Combined analysis of clinical, biochemical, and molecular data failed to indicate a correlation between the phenotype and the genotype.
KW - Cardiomyopathy
KW - Fatty acids
KW - Metabolic disease
KW - Mitochondria
KW - Mutation analysis
KW - SLC25A20
UR - http://www.scopus.com/inward/record.url?scp=5044224205&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=5044224205&partnerID=8YFLogxK
U2 - 10.1002/humu.20085
DO - 10.1002/humu.20085
M3 - Article
C2 - 15365988
AN - SCOPUS:5044224205
VL - 24
SP - 312
EP - 320
JO - Human Mutation
JF - Human Mutation
SN - 1059-7794
IS - 4
ER -