Calmodulin Methyltransferase Is Required for Growth, Muscle Strength, Somatosensory Development and Brain Function

Calmodulin lysine methyl transferase (CaM KMT) is ubiquitously expressed and highly conserved from plants to vertebrates. CaM is frequently trimethylated at Lys-115, however, the role of CaM methylation in vertebrates has not been studied. CaM KMT was found to be homozygously deleted in the 2P21 deletion syndrome that includes 4 genes. These patients present with cystinuria, severe intellectual disabilities, hypotonia, mitochondrial disease and facial dysmorphism. Two siblings with deletion of three of the genes included in the 2P21 deletion syndrome presented with cystinuria, hypotonia, a mild/moderate mental retardation and a respiratory chain complex IV deficiency. To be able to attribute the functional significance of the methylation of CaM in the mouse and the contribution of CaM KMT to the clinical presentation of the 2p21deletion patients, we produced a mouse model lacking only CaM KMT with deletion borders as in the human 2p21deletion syndrome. No compensatory activity for CaM methylation was found. Impairment of complexes I and IV, and less significantly III, of the mitochondrial respiratory chain was more pronounced in the brain than in muscle. CaM KMT is essential for normal body growth and somatosensory development, as well as for the proper functioning of the adult mouse brain. Developmental delay was demonstrated for somatosensory function and for complex behavior, which involved both basal motor function and motivation. The mutant mice also had deficits in motor learning, complex coordination and learning of aversive stimuli. The mouse model contributes to the evaluation of the role of methylated CaM. CaM methylation appears to have a role in growth, muscle strength, somatosensory development and brain function. The current study has clinical implications for human patients. Patients presenting slow growth and muscle weakness that could result from a mitochondrial impairment and mental retardation should be considered for sequence analysis of the CaM KMT gene.

钙调蛋白赖氨酸甲基转移酶（Calmodulin lysine methyl transferase，CaM KMT）广泛表达，且从植物到脊椎动物均高度保守。钙调蛋白（Calmodulin，CaM）常于赖氨酸115位点发生三甲基化修饰，但目前尚未有关于脊椎动物中CaM甲基化作用的相关研究。研究发现，CaM KMT在包含4个基因的2p21缺失综合征中存在纯合缺失。此类患者表现为胱氨酸尿症、重度智力障碍、肌张力低下、线粒体疾病及面部畸形。另有两名携带2p21缺失综合征相关3个基因缺失的同胞患者，表现为胱氨酸尿症、肌张力低下、轻中度智力障碍及呼吸链复合体IV缺陷。为明确小鼠体内CaM甲基化的功能意义，以及CaM KMT对2p21缺失综合征患者临床表现的贡献，我们构建了仅缺失CaM KMT的小鼠模型，其缺失边界与人类2p21缺失综合征一致。未发现针对CaM甲基化的代偿性活性。线粒体呼吸链复合体I、IV的功能受损，复合体III受损程度较轻，且该损伤在大脑中较肌肉中更为显著。CaM KMT对于小鼠正常的躯体生长、躯体感觉发育，以及成年小鼠大脑的正常功能均至关重要。研究证实，躯体感觉功能及涉及基础运动功能与动机的复杂行为均存在发育延迟。突变小鼠还存在运动学习、复杂协调能力及厌恶刺激学习的缺陷。本小鼠模型有助于评估甲基化钙调蛋白的功能角色。CaM甲基化似乎在生长、肌肉力量、躯体感觉发育及大脑功能中发挥作用。本研究对人类患者具有临床指导意义：对于因线粒体损伤及智力障碍导致生长迟缓、肌肉无力的患者，应考虑进行CaM KMT基因的序列分析。