Abstract
The progressive neurometabolic disorder X-linked adrenoleukodystrophy (ALD) is caused by pathogenic variants in the ABCD1 gene, which encodes the peroxisomal ATP-binding transporter for very-long-chain fatty acids. The clinical spectrum of ALD includes adrenal insufficiency, myelopathy, and/or leukodystrophy. A complicating factor in disease management is the absence of a genotype–phenotype correlation in ALD. Since 1999, most ABCD1 (likely) pathogenic and benign variants have been reported in the ABCD1 Variant Database. In 2017, following the expansion of ALD newborn screening, the database was rebuilt. To add an additional level of confidence with respect to pathogenicity, for each variant, it now also reports the number of cases identified and, where available, experimental data supporting the pathogenicity of the variant. The website also provides information on a number of ALD-related topics in several languages. Here, we provide an updated analysis of the known variants in ABCD1. The order of pathogenic variant frequency, overall clustering of disease-causing variants in exons 1–2 (transmembrane domain spanning region) and 6–9 (ATP-binding domain), and the most commonly reported pathogenic variant p.Gln472Argfs*83 in exon 5 are consistent with the initial reports of the mutation database. Novel insights include nonrandom clustering of high-density missense variant hotspots within exons 1, 2, 6, 8, and 9. Perhaps more importantly, we illustrate the importance of collaboration and utility of the database as a scientific, clinical, and ALD-community-wide resource.
Highlights
The ABCD1 gene is located on Xq28, covers 19.9 kb and contains 10 exons [1,2]
It encodes the ABCD1/ALD protein of 745 amino acids, an ATP-binding cassette transmembrane half-transporter required for the import of coenzyme A-activated very-long-chain fatty acids (VLCFAs; >C22:0) into peroxisomes for degradation [3,4]
Non-nested amplification of all exons in the ABCD1 gene using the Xq28 optimized primer sets developed by Boehm et al [17] revealed 67% of known mutations clustered into four amplicons covering 40% of the coding region: amplicon 1b in exon 1 (amino acids 75–188; 20%); amplicon 1c in exon 1; amplicon 8/9; and amplicon 5 [17]
Summary
The ABCD1 gene is located on Xq28, covers 19.9 kb and contains 10 exons [1,2] It encodes the ABCD1/ALD protein of 745 amino acids, an ATP-binding cassette transmembrane half-transporter required for the import of coenzyme A-activated very-long-chain fatty acids (VLCFAs; >C22:0) into peroxisomes for degradation [3,4]. Non-nested amplification of all exons in the ABCD1 gene using the Xq28 optimized primer sets developed by Boehm et al [17] revealed 67% of known mutations clustered into four amplicons covering 40% of the coding region: amplicon 1b in exon 1 (amino acids (aa) 75–188; 20%); amplicon 1c in exon 1 (aa 177–300; 20%); amplicon 8/9 (exons 8 and 9, aa 594–664; 14%); and amplicon 5 (exon 5, aa 465–496; 13%) [17]. Missense mutations were found at higher-than-expected frequency in exon 1 (amino acids 100–300), which code for four segments of the transmembrane domain, and at higher-than-expected frequency in exons 6–9 (amino acids 497–664), which code for the ATP-binding domain
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