Novel SLC9A6 Variation in Female Carriers With Intellectual Disability and Atypical Parkinsonism.
Novel SLC9A6 Variation in Female Carriers With Intellectual Disability and Atypical Parkinsonism.
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DOI：
10.1212/nxg.0000000000000651
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Takiyama Y
中科院分区：
文献类型：
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作者：
Nan H;Kim YJ;Tsuchiya M;Ishida A;Haro H;Hiraide M;Ohtsuka T;Takiyama Y
SLC9A6的变异导致男性的X连锁神经系统疾病Christianson综合征。同时，携带SLC9A6变异的女性携带者可能会保持无症状，或出现智力残疾、行为问题和精神疾病。据报道，只有少数女性携带者在晚年会出现非典型帕金森症。我们提出了一个日本家庭与一个新的SLC9A6变异鉴定四全外显子组测序分析和反向表型分析策略。在体外检测了W89 R变异的分子和细胞影响。SLC9A6错义变异（c.265T>C，p.Trp89Arg）与该家系女性携带者的非典型帕金森综合征和智力残疾共分离。该家族中的女性携带者表现出运动迟缓、僵硬和震颤，主要发生在右侧。我们发现W89R变异改变了NHE6携带囊泡的膜交通，表明可能参与疾病的发病机制。这项研究可能揭示了SLC9A6变异女性非典型帕金森症单基因起源的一个例子，并在临床实践中引起对这种未充分研究的女性特异性表型的注意。
Variations in SLC9A6 cause the X-linked neurologic disorder Christianson syndrome in males. Meanwhile, female carriers with SLC9A6 variations may remain asymptomatic or develop intellectual disability, behavioral problems, and psychiatric illnesses. Only a few female carriers have been reported to have associated atypical parkinsonism in late life. We present a Japanese family with a novel SLC9A6 variation identified by quad whole-exome sequencing analysis and a reverse phenotyping strategy. The molecular and cellular impacts of the W89R variation in vitro were examined. The missense variation (c.265T>C, p.Trp89Arg) in SLC9A6 cosegregated with atypical parkinsonism and intellectual disability in female carriers of this family. The female carriers in this family presented with bradykinesia, rigidity, and tremor, predominately on the right side. We found that the W89R variation changed membrane traffic of NHE6-harboring vesicles, indicating potential involvement in the disease pathogenesis. This study might have revealed an example of a monogenic origin of atypical parkinsonism in females with SLC9A6 variations and draw attention to this understudied female-specific phenotype in clinical practice.