Members of the AAA+ superfamily of ATPases are involved in the unfolding of proteins and disassembly of protein complexes and aggregates. ATAD1 encoding the ATPase family, AAA+ domain containing 1-protein Thorase plays an important role in the function and integrity of mitochondria and peroxisomes. Postsynaptically, Thorase controls the internalization of excitatory, glutamatergic AMPA receptors by disassembling complexes between the AMPA receptor-binding protein, GRIP1, and the AMPA receptor subunit GluA2. Using whole-exome sequencing, we identified a homozygous frameshift mutation in the last exon of ATAD1 [c.1070_1071delAT; p.(His357Argfs*15)] in three siblings who presented with a severe, lethal encephalopathy associated with stiffness and arthrogryposis. Biochemical and cellular analyses show that the C-terminal end of Thorase mutant gained a novel function that strongly impacts its oligomeric state, reduces stability or expression of a set of Golgi, peroxisomal and mitochondrial proteins and affects disassembly of GluA2 and Thorase oligomer complexes. Atad1^−/− neurons expressing Thorase mutant^{His357Argfs*15} display reduced amount of GluA2 at the cell surface suggesting that the Thorase mutant may inhibit the recycling back and/or reinsertion of AMPA receptors to the plasma membrane. Taken together, our molecular and functional analyses identify an activating ATAD1 mutation as a new cause of severe encephalopathy and congenital stiffness.

中文翻译：

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纯合的ATAD1突变削弱突触后AMPA受体的运输，并导致致命的脑病

ATPase AAA +超家族的成员参与蛋白质的解折叠以及蛋白质复合物和聚集体的分解。编码ATPase家族的ATAD1，含有AAA +结构域的1蛋白Thorase在线粒体和过氧化物酶体的功能和完整性中起着重要作用。突触后，Thorase通过分解AMPA受体结合蛋白GRIP1和AMPA受体亚基GluA2之间的复合物来控制兴奋性谷氨酸能AMPA受体的内在化。使用全外显子测序，我们在ATAD1的最后一个外显子中鉴定出纯合移码突变[c.1070_1071delAT; p。（His357Argfs * 15）]的三个兄弟姐妹出现了与僵硬和关节软化相关的严重致命性脑病。生化和细胞分析表明，Thorase突变体的C末端获得了一种新颖的功能，该功能强烈影响其寡聚状态，降低一组高尔基体，过氧化物酶体和线粒体蛋白的稳定性或表达，并影响GluA2和Thorase寡聚物复合物的拆卸。表达Thorase突变体^{His357Argfs * 15的}Atad1 ^-/-神经元在细胞表面显示^GluA2减少，表明Thorase突变体可能抑制AMPA受体向质膜的再循环和/或重新插入。综上所述，我们的分子和功能分析确定了ATAD1突变是严重脑病和先天性僵硬的新原因。