Mayman Naomi, Wei Jiangbo, Cai Shangjun, Soman Rohan, Raynes Hillary, La Vega-Talbott Maite, He Chuan, Naidich Thomas, Raju G Praveen, Kathiresu Nageshwaran Sathiji
Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Chemistry, University of Chicago, IL, USA.
SAGE Open Med Case Rep. 2023 Jul 29;11:2050313X231188883. doi: 10.1177/2050313X231188883. eCollection 2023.
The fat mass and obesity-associated gene () codes for a DNA/RNA demethylase. Pathological variants in this gene are rare, with only three reports in the literature, all with mutations in the catalytic domain. We report the first biallelic human variant in fat mass and obesity-associated gene (c.287G>C, p.Arg96Pro/R96P) outside the catalytic site, causing numerous abnormalities across multiple organ systems, affecting respiratory, cardiovascular, and neurological function. Biochemical assays of cells with the patient's variant were performed to further quantify the effect of the variant on function. Loss-of-function resulting from the patient's R96P missense variant was demonstrated with biochemical characterization of demethylase activity, resulting in a 90% reduction in function of the fat mass and obesity-associated protein compared to wild-type. Our findings demonstrate a novel fat mass and obesity-associated gene non-catalytic site variant with a unique patient phenotype of bilateral multifocal epilepsy and multisystem congenital anomalies.
脂肪量与肥胖相关基因（）编码一种DNA/RNA去甲基化酶。该基因的病理性变异很罕见，文献中仅有三篇报道，且所有报道中的突变均位于催化结构域。我们报告了脂肪量与肥胖相关基因中首个位于催化位点之外的双等位基因人类变异（c.287G>C，p.Arg96Pro/R96P），该变异导致多个器官系统出现众多异常，影响呼吸、心血管和神经功能。对携带患者变异的细胞进行生化分析，以进一步量化该变异对功能的影响。通过去甲基化酶活性的生化特征证明，患者的R96P错义变异导致功能丧失，与野生型相比，脂肪量与肥胖相关蛋白的功能降低了90%。我们的研究结果表明，一种新型的脂肪量与肥胖相关基因非催化位点变异具有双侧多灶性癫痫和多系统先天性异常的独特患者表型。
