TMEM163变异致髓鞘形成低下患者随访两例及iPSC构建  

Clinical Follow-up of Patients With Hypomyelinating Leukodystrophy Caused by TMEM163 Variants and Generation of The Human Induced Pluripotent Stem Cell Line From a Patient

作　　者：张钰 王君宇 段若愚 肖江喜[4] 吴晔[1,2] 姜玉武 延会芳[1,2] 王静敏 ZHANG Yu;WANG Jun-Yu;DUAN Ruo-Yu;XIAO Jiang-Xi;WU Ye;JIANG Yu-Wu;YAN Hui-Fang;WANG Jing-Min(Department of Pediatrics,Peking University First Hospital,Beijing 100034,China;Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases,Beijing 100009,China;Department of Neurology,Beijing Children’s Hospital,Capital Medical University,Beijing 100045,China;Department of Medical Imaging,Peking University First Hospital,Beijing 100034,China;Key Laboratory for Neuroscience,Ministry of Education/National Health and Family Planning Commission,Peking University,Beijing 100034,China)

机构地区：[1]北京大学第一医院儿科,北京100034 [2]儿科遗传性疾病分子诊断与研究北京市重点实验室,北京100009 [3]首都医科大学附属北京儿童医院神经内科,北京100045 [4]北京大学第一医院医学影像科,北京100034 [5]国家卫生健康委员会神经科学重点实验室,北京100034

出　　处：《生物化学与生物物理进展》2022年第11期2204-2214,共11页Progress In Biochemistry and Biophysics

基　　金：儿科遗传性疾病分子诊断与研究北京市重点实验室(BZ0317);北京大学医学部-密歇根大学医学院转化医学与临床研究联合研究所(BMU2019JI009);国家自然科学基金(82071264,82101941)资助项目。

摘　　要：目的探讨TMEM163变异导致髓鞘形成低下性脑白质营养不良(HLD)患者的临床特征及遗传学特点,归纳自然病程,以提高对该疾病认识,并构建患者来源诱导多能干细胞,为致病机制研究建立基础。方法随访2009~2022年北京大学第一医院儿科就诊的2例TMEM163变异致病患儿,对临床表现、遗传学数据、蛋白质结构数据进行分析,总结临床遗传学特点,并采集患儿外周血构建诱导多能干细胞。结果临床特点:2例患儿均具有早期运动语言发育迟缓、头颅磁共振成像显示脑白质髓鞘化不良,且症状随生长发育逐渐减轻的特点;均于婴儿期起病,以眼球震颤为首发症状,学龄期症状好转。遗传学特点:2例患儿均为TMEM163同一位点新发错义变异c.227T>G p.(L76R)、c.227T>C p.(L76P),均为国际上首例报道。病例2来源外周血单个核细胞成功重编程为诱导多能干细胞。结论本研究为国际首次随访TMEM163变异致病髓鞘形成低下性脑白质营养不良患儿,完善了其自然病程,扩展了对髓鞘形成低下性脑白质营养不良临床表型认识,并首次构建了TMEM163 c.227T>C p.(L76P)变异患者来源诱导多能干细胞,为进一步致病机制研究打下基础。Objective To explore the clinical and genetic characteristics of patients with hypomyelinating leukodystrophy caused by TMEM163 mutation,track the natural history of the disease,and to construct patientderived induced pluripotent stem cells,thus laying the foundation for mechanism research.Methods Clinical and genetic data of two patients(Pt1,Pt2)with TMEM163 mutation were collected from 2009 to 2022 in Department of Pediatrics,Peking University First Hospital.The clinical manifestations,genetic data,and protein structure data were analyzed.Peripheral blood of Pt2 was collected to construct induced pluripotent stem cell(iPSC).Results Clinical features:both patients showed early motor and language development retardation and hypomyelination abnormalities from brain magnetic resonance imaging(MRI),however,the symptoms gradually alleviated;nystagmus was the first symptom,abnormal gait,low muscle tone and mild to moderate developmental retardation were observed in both of them;Pt1 has the same growth and development level as children of the same age at 7 years old.Genetic features:both cases were newly detected missense variants at the same locus of TMEM163 c.227T>G p.(L76R),c.227T>C p.(L76P).The differentiation of iPSC induced by peripheral blood monocytes from Pt2 was consistent with the characteristics of iPSC.Conclusion The follow-up study of 2 children with HLD contributes to the understanding of the natural history of HLD caused TMEM163 mutation,expands the understanding of the clinical phenotype of HLD,and constructs TMEM163 c.227T>C p.(L76P)iPSC,which lays a foundation for the mechanism study.

关 键 词：TMEM163 人诱导多能干细胞 髓鞘形成低下性脑白质营养不良 随访研究 

分 类 号：R72[医药卫生—儿科]