Camacho José A, Rioseco-Camacho Natalia
Department of Pediatrics, University of California-Irvine, Irvine, CA 92697, USA.
Pediatr Res. 2009 Jul;66(1):35-41. doi: 10.1203/PDR.0b013e3181a283c1.
The hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a disorder of the urea cycle (UCD) and ornithine degradation pathway caused by mutations in the mitochondrial ornithine transporter (ORNT1). Unlike other UCDs, HHH syndrome is characterized by a less severe and variable phenotype that we believe may, in part, be due to genes with redundant function to ORNT1, such as the previously characterized ORNT2 gene. We reasoned that SLC25A29, a member of the same subfamily of mitochondrial carrier proteins as ORNT1 and ORNT2, might also have overlapping function with ORNT1. Here, we report that both the human and mouse SLC25A29, previously identified as mitochondrial carnitine/acyl-carnitine transporter-like, when overexpressed transiently also rescues the impaired ornithine transport in cultured HHH fibroblasts. Moreover, we observed that, in the mouse, the Slc25a29 message is more significantly expressed in the CNS and cultured astrocytes when compared with the liver and kidney. These results suggest a potential physiologic role for the SLC25A29 transporter in the oxidation of fatty acids, ornithine degradation pathway, and possibly the urea cycle. Our results show that SLC25A29 is the third human mitochondrial ornithine transporter, designated as ORNT3, which may contribute to the milder and variable phenotype seen in patients with HHH syndrome.
高鸟氨酸血症-高氨血症-同型瓜氨酸尿症（HHH）综合征是一种尿素循环（UCD）和鸟氨酸降解途径的紊乱疾病，由线粒体鸟氨酸转运体（ORNT1）突变引起。与其他UCD不同，HHH综合征的特征是表型较轻且具有变异性，我们认为这可能部分归因于与ORNT1具有冗余功能的基因，例如先前已鉴定的ORNT2基因。我们推测，SLC25A29作为与ORNT1和ORNT2属于同一家族的线粒体载体蛋白成员，可能也与ORNT1具有重叠功能。在此，我们报告，先前被鉴定为线粒体肉碱/酰基肉碱转运体样的人类和小鼠SLC25A29，当瞬时过表达时，也能挽救培养的HHH成纤维细胞中受损的鸟氨酸转运。此外，我们观察到，在小鼠中，与肝脏和肾脏相比，Slc25a29在中枢神经系统和培养的星形胶质细胞中表达更为显著。这些结果表明SLC25A29转运体在脂肪酸氧化、鸟氨酸降解途径以及可能的尿素循环中具有潜在的生理作用。我们的结果表明，SLC25A29是人类第三个线粒体鸟氨酸转运体，命名为ORNT3，它可能导致HHH综合征患者出现较轻且多变的表型。
