Structure and Function of the ABCD1 Variant Database: 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy.
Structure and Function of the ABCD1 Variant Database: 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy.
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作者：
Mallack EJ;Gao K;Engelen M;Kemp S
进行性神经代谢障碍X连锁肾上腺脑白质营养不良（ALD）是由ABCD 1基因的致病性变体引起的，ABCD 1基因编码过氧化物酶体ATP结合转运蛋白，用于极长链脂肪酸。ALD的临床谱包括肾上腺功能不全、脊髓病和/或脑白质营养不良。疾病管理中的一个复杂因素是ALD中缺乏基因型-表型相关性。自1999年以来，大多数ABCD 1（可能）致病性和良性变异已在ABCD 1变异数据库中报告。2017年，随着ALD新生儿筛查的扩大，数据库得到重建。为了增加致病性的可信度，对于每一种变异，它现在还报告已查明的病例数，并在现有情况下报告支持变异致病性的实验数据。该网站还以几种语文提供有关限期休假的一些专题的信息。在这里，我们提供了ABCD 1已知变体的最新分析。致病性变异频率的顺序、致病性变异在外显子1-2（跨膜结构域跨越区）和6-9（ATP结合结构域）中的总体聚类以及最常报告的致病性变异在外显子5中的p.Gln472Argfs*83与突变数据库的初始报告一致。新的见解包括外显子1，2，6，8和9内的高密度错义变体热点的非随机聚类。也许更重要的是，我们说明了合作的重要性和效用的数据库作为一个科学，临床和ALD社区范围内的资源。
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.
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DOI：
10.1056/nejmoa1700554
发表时间：
2017-10-26
期刊：
The New England journal of medicine
影响因子：
--
作者：
Eichler F;Duncan C;Musolino PL;Orchard PJ;De Oliveira S;Thrasher AJ;Armant M;Dansereau C;Lund TC;Miller WP;Raymond GV;Sankar R;Shah AJ;Sevin C;Gaspar HB;Gissen P;Amartino H;Bratkovic D;Smith NJC;Paker AM;Shamir E;O'Meara T;Davidson D;Aubourg P;Williams DA
通讯作者：
Williams DA
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
1.5
作者：
Henig I;Zuckerman T
通讯作者：
Zuckerman T
影响因子：
2.2
作者：
Beckmann, Nicole B.;Miller, Weston P.;Orchard, Paul J.
通讯作者：
Orchard, Paul J.
DOI：
10.1006/bbrc.1994.1979
发表时间：
1994-07-29
影响因子：
3.1
作者：
KEMP, S;LIGTENBERG, MJL;BOLHUIS, PA
通讯作者：
BOLHUIS, PA