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Article

Structure and Function of the ABCD1 Variant Database: 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy

1
Department of Pediatrics, Division of Child Neurology, Weill Cornell Medical College, NewYork-Presbyterian Hospital, New York, NY 10065, USA
2
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
3
Department of Pediatric Neurology, Emma Children’s Hospital, Amsterdam University Medical Centers, Amsterdam Neuroscience, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
4
Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam University Medical Center, Amsterdam Gastroenterology Endocrinology Metabolism, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
*
Author to whom correspondence should be addressed.
Academic Editors: Joseph G. Hacia and William B. Rizzo
Cells 2022, 11(2), 283; https://doi.org/10.3390/cells11020283
Received: 17 November 2021 / Revised: 11 January 2022 / Accepted: 12 January 2022 / Published: 14 January 2022
(This article belongs to the Special Issue Peroxisomal Disorders: Development of Targeted Therapies)
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. View Full-Text
Keywords: adrenoleukodystrophy; peroxisome; ABC transporter; newborn screening; genetics; diagnosis; mutation; variants of uncertain significance; ABCD1 adrenoleukodystrophy; peroxisome; ABC transporter; newborn screening; genetics; diagnosis; mutation; variants of uncertain significance; ABCD1
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MDPI and ACS Style

Mallack, E.J.; Gao, K.; Engelen, M.; Kemp, S. Structure and Function of the ABCD1 Variant Database: 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy. Cells 2022, 11, 283. https://doi.org/10.3390/cells11020283

AMA Style

Mallack EJ, Gao K, Engelen M, Kemp S. Structure and Function of the ABCD1 Variant Database: 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy. Cells. 2022; 11(2):283. https://doi.org/10.3390/cells11020283

Chicago/Turabian Style

Mallack, Eric J., Kerry Gao, Marc Engelen, and Stephan Kemp. 2022. "Structure and Function of the ABCD1 Variant Database: 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy" Cells 11, no. 2: 283. https://doi.org/10.3390/cells11020283

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