A novel SLC25A20 splicing mutation in patients of different ethnic origin with neonatally lethal carnitine-acylcarnitine translocase (CACT) deficiency
- 作者：Stanley H. Korman ; James J. Pitt ; Avihu Boneh ; Imad Dweikat ; Mokhtar Zater ; Vardiella Meiner ; Alisa Gutman ; Michè ; le Brivet
- 关键词：Carnitine-acylcarnitine carrier ; Mitochondrial fatty acid oxidation ; Prenatal diagnosis ; Post-mortem diagnosis ; Mutation analysis ; Splice mutation ; Carnitine/metabolism ; Newborn
- 刊名：Molecular Genetics and Metabolism
- 出版年：2006
- 期刊代码：175_10967192
- 类别：bio
- 出版时间：December 2006
- 卷：89
- 期：4
- 页码：332-338
- 文件大小：327 K
摘要
Carnitine-acylcarnitine translocase (CACT) deficiency is a rare disorder of fatty acid oxidation associated with high mortality. Two female newborns of different ethnic origin (the first Anglo-Celtic and the second Palestinian Arab) both died after sudden collapse on day 2 of life. Both had elevated bloodspot long-chain acylcarnitines consistent with either CACT or carnitine palmitoyltransferase II (CPT2) deficiency; the latter was excluded by demonstrating normal CPT2 activity in fibroblasts. Direct sequencing of all SLC25A20 (CACT) gene exons and exon–intron boundaries revealed that Patient 1 was compound heterozygous for a novel c.609-3c > g (IVS6-3c > g) mutation on the paternal allele and a previously described c.326delG mutation on the maternal allele. Patient 2 was homozygous for the same, novel c.609-3c > g mutation. Previously reported SLC25A20 mutations have been almost exclusively confined to a single family or ethnic group. Analysis of fibroblast cDNA by RT-PCR, agarose gel electrophoresis and sequencing of extracted bands showed that both mutations produce aberrant splicing. c.609-3C > G results in exon 7 skipping leading to a frameshift with premature termination seven amino acids downstream. c.326delG was confirmed to produce skipping of exons 3 or 3 plus 4. CACT activity in both patients’ fibroblasts was near-zero. For both families, prenatal diagnosis of an unaffected fetus was performed by mutation analysis on CVS tissue in a subsequent pregnancy. Due to the urgency of prenatal diagnosis in the second family, molecular diagnosis was performed prior to demonstration of CACT enzyme deficiency, illustrating that mutation analysis is a rapid and reliable approach to first-line diagnosis of CACT deficiency.