Loss-of-function mutation of ABCC9, the gene encoding the SUR2 subunit of ATP sensitive-potassium (KATP) channels, was recently associated with autosomal recessive ABCC9-related intellectual disability and myopathy syndrome (AIMS). Here we identify nine additional subjects, from seven unrelated families, harboring different homozygous LoF variants in ABCC9 and presenting with a conserved range of clinical features. All variants are predicted to result in severe truncations or in-frame deletions within SUR2, leading to the generation of non-functional SUR2-dependent KATP channels. Affected individuals show psychomotor delay and intellectual disability of variable severity, microcephaly, corpus callosum and white matter abnormalities, seizures, spasticity, short stature, muscle fatigability, and weakness. Heterozygous parents do not show any conserved clinical pathology but report multiple incidences of intrauterine fetal death, which were also observed in an eighth family included in this study. In vivo studies of abcc9 LoF in zebrafish revealed an exacerbated motor response to pentylenetetrazole, a pro-convulsive drug, consistent with impaired neurodevelopment associated with an increased seizure susceptibility. Our findings define an ABCC9 LoF related phenotype, expanding the genotypic and phenotypic spectrum of AIMS and reveal novel human pathologies arising from KATP channel dysfunction.

中文翻译：

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新型功能丧失变异扩大了 ABCC9 相关的智力障碍和肌病综合征

ABCC9 是编码 ATP 敏感钾 (KATP) 通道 SUR2 亚基的基因，其功能丧失突变最近与常染色体隐性 ABCC9 相关的智力障碍和肌病综合征 (AIMS) 相关。在这里，我们确定了另外 9 名受试者，他们来自 7 个不相关的家族，在 ABCC9 中携带不同的纯合 LoF 变异，并表现出一系列保守的临床特征。预计所有变异都会导致 SUR2 内严重截断或框内删除，从而导致非功能性 SUR2 依赖性 KATP 通道的生成。受影响的个体表现出不同严重程度的精神运动迟缓和智力障碍、小头畸形、胼胝体和白质异常、癫痫发作、痉挛、身材矮小、肌肉疲劳和虚弱。杂合子父母没有表现出任何保守的临床病理学，但报告了多次宫内胎儿死亡的发生率，在本研究中的第八个家庭中也观察到了这种情况。斑马鱼 abcc9 LoF 的体内研究揭示了对促惊厥药物戊四唑的运动反应加剧，这与癫痫易感性增加相关的神经发育受损一致。我们的研究结果定义了 ABCC9 LoF 相关表型，扩展了 AIMS 的基因型和表型谱，并揭示了 KATP 通道功能障碍引起的新的人类病理学。