ABCC9的功能缺失突变,该基因编码ATP敏感钾(KATP)通道的SUR2亚基,最近与常染色体隐性遗传ABCC9相关的智力障碍和肌病综合征(AIMS)相关。在这里,我们确定了九个额外的主题,来自七个不相关的家庭,在ABCC9中具有不同的纯合LoF变体,并具有保守的临床特征。预测所有变体导致SUR2内的严重截短或框内缺失,导致非功能性SUR2依赖性KATP通道的产生。受影响的个体表现出不同严重程度的精神运动延迟和智力残疾,小头畸形,call体和白质异常,癫痫发作,痉挛,身材矮小,肌肉疲劳,和弱点。杂合的父母没有显示任何保守的临床病理,但报告多次发生宫内胎儿死亡,在本研究中纳入的第八个家庭中也观察到了这一点。斑马鱼abcc9LoF的体内研究揭示了对戊四唑的加剧的运动反应,一种促惊厥的药物,与癫痫发作易感性增加相关的神经发育受损一致。我们的发现定义了ABCC9LoF相关表型,扩展AIMS的基因型和表型谱,并揭示由KATP通道功能障碍引起的新型人类病理。
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, harbouring different homozygous loss-of-function 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 intra-uterine fetal death, which were also observed in an eighth family included in this study. In vivo studies of
abcc9 loss-of-function 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 loss-of-function-related phenotype, expanding the genotypic and phenotypic spectrum of AIMS and reveal novel human pathologies arising from KATP channel dysfunction.