Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters

Abstract

Adrenoleukodystrophy (ALD) is an X-linked disease affecting 1/20,000 males either as cerebral ALD in childhood or as adrenomyeloneuropathy (AMN) in adults. Childhood ALD is the more severe form, with onset of neurological symptoms between 5-12 years of age. Central nervous system demyelination progresses rapidly and death occurs within a few years. AMN is a milder form of the disease with onset at 15-30 years of age and a more progressive course. Adrenal insufficiency (Addison's disease) may remain the only clinical manifestation of ALD. The principal biochemical abnormality of ALD is the accumulation of very-long-chain fatty acids (VLCFA) because of impaired beta-oxidation in peroxisomes. The normal oxidation of VLCFA-CoA in patients' fibroblasts suggested that the gene coding for the VLCFA-CoA synthetase could be a candidate gene for ALD. Here we use positional cloning to identify a gene partially deleted in 6 of 85 independent patients with ALD. In familial cases, the deletions segregated with the disease. An identical deletion was detected in two brothers presenting with different clinical ALD phenotypes. Candidate exons were identified by computer analysis of genomic sequences and used to isolate complementary DNAs by exon connection and screening of cDNA libraries. The deduced protein sequence shows significant sequence identity to a peroxisomal membrane protein of M(r) 70K that is involved in peroxisome biogenesis and belongs to the 'ATP-binding cassette' superfamily of transporters.

The motor domains of ABC-transporters

“…The Dubin-Johnson syndrome is conferred by mutations in the ABCC2 gene, leading to a deficiency in canalicular multispecific organic anion transport and bilirubin accumulation in liver (Wada et al 1998). Long chain fatty acids are transported by ABCD1, and Adrenoleukodystrophy (ADL) is a genetically inherited disease, caused by mutations in the ABCD1 gene (Mosser et al 1993). Finally, the ABCG2 transporter is also overexpressed in human cancer cells, resulting in multidrug resistance independent of the classic multidrug transporters MDR1 and MRP1 (Robey et al 2001).…”

Microglial dysfunction as a key pathological change in adrenomyeloneuropathy

“…X‐linked adrenoleukodystrophy (X‐ALD) is caused by mutations in ABCD1 , a gene that encodes the peroxisomal half‐transporter adenosine triphosphate‐binding cassette domain I (ABCD1) 1, 2. The most severe form of X‐ALD, childhood cerebral ALD (CALD), manifests as acute demyelination in childhood with prominent lymphocytic infiltration and a distinct zone of microglial cell death surrounding the inflammatory lesion 3, 4.…”

Peroxisomes: simple in function but complex in maintenance

“…The first transporter molecules to be identified were the ABC half-transporters Pat1p and Pat2p of Saccharomyces cerevisiae. These proteins are homologous to the human peroxisomal ABC transporter, which, when mutated, is responsible for X-linked adrenoleukodystrophy 5,6 . In-depth analysis of the function of Pat1p and Pat2p in yeast suggests that they are important for the translocation of long-chain acyl-CoA esters across the peroxisomal membrane for subsequent ␤-oxidation within the peroxisomal matrix 7,8 .…”