Do PACS1 variants impeding adaptor protein binding predispose to syndromic intellectual disability?
Do PACS1 variants impeding adaptor protein binding predispose to syndromic intellectual disability?
复制标题
DOI：
10.1002/ajmg.a.63232
复制
发表时间：
2023-05
影响因子：
2
通讯作者：
Ashley Moller-Hansen;Duha Hejla;Hyun Kyung Lee;J. Lyles;Yunhan Yang;Kun Chen;W. L. Li;G. Thomas;C. Boerkoel
中科院分区：
文献类型：
--
作者：
Ashley Moller-Hansen;Duha Hejla;Hyun Kyung Lee;J. Lyles;Yunhan Yang;Kun Chen;W. L. Li;G. Thomas;C. Boerkoel
到目前为止，PACS1-神经发育障碍(PACS1-NDD)与Arg203的反复变异有关，被认为是PACS1-NDD的诊断，PACS1-NDD是一种常染色体显性遗传性智力障碍。虽然还不完全确定，但这种变异体的致病机制是其客户蛋白的PACS1亲和力改变。鉴于这一提出的机制，我们假设干扰接头蛋白结合的PACS1变体也可能导致综合征性智能障碍。在这里，我们报告了一位先证者和她的母亲，其表型特征与PACS1NDD和一个新的PACS1变异体(NM_018026.3：c.[755C>；T]；[=]，p.(Ser252Phe))重叠，该变异体阻碍适配蛋白GGA3(高尔基相关的、伽马适应素耳内含ARF结合蛋白3)的结合。我们假设，减弱GGA3的PACS1结合也会引起一种功能紊乱，其特征与PACS1-NDD重叠。这一观察结果更好地描述了PACS1变异导致综合征性智能障碍的机制。
To date, PACS1‐neurodevelopmental disorder (PACS1‐NDD) has been associated with recurrent variation of Arg203 and is considered diagnostic of PACS1‐NDD, an autosomal dominant syndromic intellectual disability disorder. Although incompletely defined, the proposed disease mechanism for this variant is altered PACS1 affinity for its client proteins. Given this proposed mechanism, we hypothesized that PACS1 variants that interfere with binding of adaptor proteins might also give rise to syndromic intellectual disability. Herein, we report a proposita and her mother with phenotypic features overlapping PACS1‐NDD and a novel PACS1 variant (NM_018026.3:c.[755C > T];[=], p.(Ser252Phe)) that impedes binding of the adaptor protein GGA3 (Golgi‐associated, gamma‐adaptin ear‐containing, ARF‐binding protein 3). We hypothesize that attenuating PACS1 binding of GGA3 also gives rise to a disorder with features overlapping those of PACS1‐NDD. This observation better delineates the mechanism by which PACS1 variation predisposes to syndromic intellectual disability.