A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3

Abstract

ABCD3 is one of three ATP-binding cassette (ABC) transporters present in the peroxisomal membrane catalyzing ATP-dependent transport of substrates for metabolic pathways localized in peroxisomes. So far, the precise function of ABCD3 is not known. Here, we report the identification of the first patient with a defect of ABCD3. The patient presented with hepatosplenomegaly and severe liver disease and showed a striking accumulation of peroxisomal C27-bile acid intermediates in plasma. Investigation of peroxisomal parameters in skin fibroblasts revealed a reduced number of enlarged import-competent peroxisomes. Peroxisomal beta-oxidation of C26:0 was normal, but beta-oxidation of pristanic acid was reduced. Genetic analysis revealed a homozygous deletion at the DNA level of 1758bp, predicted to result in a truncated ABCD3 protein lacking the C-terminal 24 amino acids (p.Y635NfsX1). Liver disease progressed and the patient required liver transplantation at 4 years of age but expired shortly after transplantation. To corroborate our findings in the patient, we studied a previously generated Abcd3 knockout mouse model. Abcd3-/- mice accumulated the branched chain fatty acid phytanic acid after phytol loading. In addition, analysis of bile acids revealed a reduction of C24 bile acids, whereas C27-bile acid intermediates were significantly increased in liver, bile and intestine of Abcd3-/- mice. Thus, both in the patient and in Abcd3-/- mice, there was evidence of a bile acid biosynthesis defect. In conclusion, our studies show that ABCD3 is involved in transport of branched-chain fatty acids and C27 bile acids into the peroxisome and that this is a crucial step in bile acid biosynthesis.

Hepatic dysfunction in peroxisomal disorders

“…However, liver pathology due to defective peroxisomal β-oxidation can be life threatening as exemplified by a single patient with ABCD3 deficiency (also known as PMP70) who presented with hepatosplenomegaly at 1.5 years of age. Liver further enlarged and became cirrhotic at age of 5 years, necessitating liver transplantation, but the patient died due to respiratory complications [35]. In a few patients with AMACR deficiency cholestatic liver disease developed in childhood with malabsorption of fat soluble vitamins [36].…”

“…Summarizing, similar to the PBD patients, the liver phenotype is subordinate to the nervous system dysfunction in severely affected neonates and infants with peroxisomal β-oxidation deficiency. However, liver failure in the absence of nervous deficits can occur in older patients as illustrated by the clinical course of the single PMP70 patient reported to date [35].…”

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

“…This implies that phytanoyl-CoA is the most likely substrate to be transported across the peroxisomal membrane. Based on our own recent work in a patient with a genetic defect in ABCD3 coding for PMP70 as well as studies in a mutant Abcd3(-/-) mouse model we conclude that PMP70 (ABCD3) catalyzes the uptake of phytanoyl-CoA into peroxisomes (Ferdinandusse et al, 2015; see Figure 9). Once inside the peroxisome interior, phytanoyl-CoA is hydroxylated by the enzyme phytanoyl-CoA 2-hydroxylase first identified by Mihalik et al (1995) to produce 2-hydroxyphytanoyl-CoA.…”

“…Activation of DHCA and THCA produced by the mitochondrial enzyme CYP27A1 most likely occurs by the ER enzyme bile acidCoA ligase (BACL) encoded by SLC27A5 (Wheeler et al, 1997;Falany et al, 2002) after which the two CoA-esters of DHCA and THCA enter the peroxisome. The recent identification of PMP70 deficiency in a patient with markedly elevated DHCA and THCA levels in plasma supported by additional studies in the Pmp70(-/-/) mouse has led to the conclusion that the peroxisomal half-ABC-transporter PMP70 (ABCD3) catalyzes the import of these acyl-CoAs into peroxisomes (Ferdinandusse et al, 2015). The actual beta-oxidation of DHC-CoA and THC-CoA is catalyzed by the enzymes ACOX2, D-bifunctional protein, and peroxisomal thiolase-2 (SCPx) (see Figure 4).…”

“…The essential role of peroxisomes in each of these metabolic pathways is emphasized by the fact that a variety of genetic diseases in man has been identified, usually with severe clinical signs and symptoms, that are caused by mutations in genes coding for peroxisomal enzymes involved in each of these metabolic pathways. Table 1 lists the single peroxisomal enzyme deficiencies identified so far including two recently identified peroxisomal disorders including fatty acyl-CoA reductase 1 (FAR1) deficiency (Buchert et al, 2014) and Peroxisomal Membrane Protein 70 (PMP70/ABCD3) deficiency (Ferdinandusse et al, 2015).…”