Table_1_Functional and Structural Changes in the Membrane-Bound O-Acyltransferase Family Member 7 (MBOAT7) Protein: The Pathomechanism of a Novel MBOAT7 Variant in Patients With Intellectual Disability.DOCX

The membrane-bound O-acyltransferase domain-containing 7 (MBOAT7) gene is associated with intellectual disability, early onset seizures, and autism spectrum disorders. This study aimed to determine the pathogenetic mechanism of the MBOAT7 missense variant via molecular modeling. Three patients from a consanguineous family were found to have a homozygous c.757G>A (p.Glu253Lys) variant of MBOAT7. The patients showed prominent dysfunction in gait, swallowing, vocalization, and fine motor function and had intellectual disabilities. Brain magnetic resonance imaging showed signal changes in the bilateral globus pallidi and cerebellar dentate nucleus, which differed with age. In the molecular model of human MBOAT7, Glu253 in the wild-type protein is located close to the backbone carbonyl oxygens in the loop near the helix, suggesting that the ionic interaction could contribute to the conformational stability of the funnel. Molecular modeling showed that Lys253 in the mutant protein was expected to alter the surface charge distribution, thereby potentially affecting substrate specificity. Changes in conformational stability and substrate specificity through varied ionic interactions are the suggested pathophysiological mechanisms of the MBOAT7 variant found in patients with intellectual disabilities.

含膜结合O-酰基转移酶结构域7（MBOAT7）基因与智力障碍、早发性癫痫及自闭症谱系障碍密切相关。本研究旨在通过分子建模手段，阐明MBOAT7错义变异的致病机制。研究团队从一个近亲婚配家族中，鉴定出3名携带MBOAT7纯合子c.757G>A（p.Glu253Lys）变异的患者。上述患者表现出显著的步态、吞咽、发声及精细运动功能障碍，并伴有智力障碍。脑部磁共振成像结果显示，双侧苍白球与小脑齿状核存在信号异常改变，且该改变随年龄呈现动态变化。在人类MBOAT7的分子模型中，野生型蛋白的Glu253位点紧邻螺旋附近环结构的主链羰基氧，提示离子相互作用或可维持该漏斗状结构域的构象稳定性。分子建模分析表明，突变蛋白中的Lys253位点会改变蛋白表面电荷分布，进而可能影响底物特异性。综上，通过改变离子相互作用引发的构象稳定性与底物特异性变化，被认为是本研究中智力障碍患者所携带MBOAT7变异的潜在病理生理机制。