An AP4B1 frameshift mutation in siblings with intellectual disability and spastic tetraplegia further delineates the AP-4 deficiency syndrome
An AP4B1 frameshift mutation in siblings with intellectual disability and spastic tetraplegia further delineates the AP-4 deficiency syndrome
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DOI：
10.1038/ejhg.2014.73
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发表时间：
2015-02-01
影响因子：
5.2
通讯作者：
Kutsche, Kerstin
中科院分区：
文献类型：
--
作者：
Abdollahpour, Hengameh;Alawi, Malik;Kutsche, Kerstin
最近提出的接头蛋白 4 (AP-4) 缺乏综合征包括一组先天性神经系统疾病，其特征为严重智力障碍 (ID)、言语迟缓或缺席、遗传性痉挛性截瘫和生长迟缓。 AP-4 是一种异四聚体蛋白复合物，在囊泡运输中具有重要功能。据报道，在 AP-4 缺陷表型患者中，影响 AP-4 不同亚基（包括 AP4B1、AP4E1、AP4S1 和 AP4M1）的基因突变。我们描述了一对非近亲夫妇的两个兄弟姐妹，他们患有严重的智障、失语、小头畸形、生长迟缓和进行性痉挛性四肢瘫痪。两名患者的全外显子组测序鉴定出 AP4B1 中新的纯合 2-bp 缺失 c.1160_1161delCA (p.(Thr387Argfs*30))。桑格测序证实了兄弟姐妹中的突变，并揭示了父母双方的杂合状态。 AP4B1 相关表型先前已被指定为痉挛性截瘫 47。在两名患者中鉴定出新的 AP4B1 改变，其临床表现与其他具有影响四个 AP-4 亚基之一的突变的个体高度相似，进一步支持了这样的观察：AP-4 组装或功能的丧失是这些患者常见临床特征的基础，并强调了临床上可识别的 AP-4 缺乏综合征的存在。
The recently proposed adaptor protein 4 (AP-4) deficiency syndrome comprises a group of congenital neurological disorders characterized by severe intellectual disability (ID), delayed or absent speech, hereditary spastic paraplegia, and growth retardation. AP-4 is a heterotetrameric protein complex with important functions in vesicle trafficking. Mutations in genes affecting different subunits of AP-4, including AP4B1, AP4E1, AP4S1, and AP4M1, have been reported in patients with the AP-4 deficiency phenotype. We describe two siblings from a non-consanguineous couple who presented with severe ID, absent speech, microcephaly, growth retardation, and progressive spastic tetraplegia. Whole-exome sequencing in the two patients identified the novel homozygous 2-bp deletion c.1160_1161delCA (p.(Thr387Argfs*30)) in AP4B1. Sanger sequencing confirmed the mutation in the siblings and revealed it in the heterozygous state in both parents. The AP4B1-associated phenotype has previously been assigned to spastic paraplegia-47. Identification of a novel AP4B1 alteration in two patients with clinical manifestations highly similar to other individuals with mutations affecting one of the four AP-4 subunits further supports the observation that loss of AP-4 assembly or functionality underlies the common clinical features in these patients and underscores the existence of the clinically recognizable AP-4 deficiency syndrome.