Exome Sequencing Reveals De Novo WDR45 Mutations Causing a Phenotypically Distinct, X-Linked Dominant Form of NBIA
Exome Sequencing Reveals De Novo WDR45 Mutations Causing a Phenotypically Distinct, X-Linked Dominant Form of NBIA
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DOI：
10.1016/j.ajhg.2012.10.019
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发表时间：
2012-12-07
影响因子：
9.8
通讯作者：
Hayflick, Susan J.
中科院分区：
文献类型：
--
作者：
Haack, Tobias B.;Hogarth, Penelope;Hayflick, Susan J.
脑铁积累性神经退行性变（NBIA）是一组以基底神经节铁沉积异常为特征的遗传性疾病。我们报告，WDR45（一种位于 Xp11.23 的基因，编码在自噬中具有推定作用的 β-螺旋桨支架蛋白）的从头突变会导致独特的 NBIA 表型。临床特征包括早发性整体发育迟缓和进一步的神经系统恶化（帕金森症、肌张力障碍和成年早期发生的痴呆）。脑部 MRI 显示黑质和苍白球有铁沉积的证据。男性和女性在表型上相似，这一观察结果可能是通过幸存男性的体细胞嵌合体和女性的种系或体细胞突变以及X染色体失活的倾斜来解释的。这种临床上可识别的疾病是 NBIA 的更常见形式之一，我们建议将其相应地命名为 β-螺旋桨蛋白相关神经变性。
Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic disorders characterized by abnormal iron deposition in the basal ganglia. We report that de novo mutations in WDR45, a gene located at Xp11.23 and encoding a beta-propeller scaffold protein with a putative role in autophagy, cause a distinctive NBIA phenotype. The clinical features include early-onset global developmental delay and further neurological deterioration (parkinsonism, dystonia, and dementia developing by early adulthood). Brain MRI revealed evidence of iron deposition in the substantia nigra and globus pallidus. Males and females are phenotypically similar, an observation that might be explained by somatic mosaicism in surviving males and germline or somatic mutations in females, as well as skewing of X chromosome inactivation. This clinically recognizable disorder is among the more common forms of NBIA, and we suggest that it be named accordingly as beta-propeller protein-associated neurodegeneration.