伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病一家系中NOTCH3基因的新突变
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摘要
目的:探讨伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病(CADASIL)基因的新突变。方法:对一CADASIL先证者的家系信息进行调查和分析。对先证者进行皮肤组织活检。应用高通量测序的方法对2例患者及先证者子女进行突变基因检测。结果:电镜下,皮肤组织小动脉管壁平滑肌细胞膜和膜外基质间可见多个嗜锇颗粒沉积。家系中现存2例患者及先证者子女NOTCH3基因第6号外显子区存在一处杂合突变(c. 811T>C),导致相应氨基酸发生改变(半胱氨酸>精氨酸),迄今为止,HGMDpro数据库未见此类突变。结论:NOTCH3基因第6号外显子的杂合错义突变(c. 811T> C)为新的突变类型,是CADASIL的致病突变。
Aim: To analyze mutation of NOTCH3 gene in one Chinese family of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy( CADASIL) and the possible pathogenesis. Methods: The family information of one CADASIL family was collected and analyzed. Skin biopsy of the proband was performed. To detect mutant gene,target region capture and high-throughput sequencing were used,and interpreted the data viariation according to the guidelines of the American College of Medical Genetics and Genomics( ACMG). Results: Under electron microscopy,osmiophilic granules deposited between smooth muscle cell membrane and extramembranous matrix of arteriole wall in skin tissue were found. The gene test of the offsprings of the proband and 2 patients with CADASIL in this family showed that a heterozygous mutation was found in the exon 6 region of NOTCH3 gene( c. 811 T > C),which caused the change of corresponding amino acid( cysteine > arginine). Up to now,this mutation has never been reported by HGMDpro database. Conclusion: The heterozygous missense mutation( c. 811 T > C) in exon 6 of NOTCH3 gene is a new mutation type,which is the pathogenic mutation of CADASIL.
Aim: To analyze mutation of NOTCH3 gene in one Chinese family of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy( CADASIL) and the possible pathogenesis. Methods: The family information of one CADASIL family was collected and analyzed. Skin biopsy of the proband was performed. To detect mutant gene,target region capture and high-throughput sequencing were used,and interpreted the data viariation according to the guidelines of the American College of Medical Genetics and Genomics( ACMG). Results: Under electron microscopy,osmiophilic granules deposited between smooth muscle cell membrane and extramembranous matrix of arteriole wall in skin tissue were found. The gene test of the offsprings of the proband and 2 patients with CADASIL in this family showed that a heterozygous mutation was found in the exon 6 region of NOTCH3 gene( c. 811 T > C),which caused the change of corresponding amino acid( cysteine > arginine). Up to now,this mutation has never been reported by HGMDpro database. Conclusion: The heterozygous missense mutation( c. 811 T > C) in exon 6 of NOTCH3 gene is a new mutation type,which is the pathogenic mutation of CADASIL.
引文
[1] RUTTEN JW, KLEVER RR, HEGEMAN IM,et al.NOTCH3 score:a pre-clinical CADASIL biomaker in a novel human genomic NOTCH3 transgenic mouse model with early progressive vascular NOTCH3 accumulation[J]. Acta Neuropathol Commun,2015,3:89
[2] CHOUDHARY S,MCL EM,TORCHIA D,et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL)[J]. J Clin Aesthet Dermatol,2013,6(3):29
[3] STOGANOV D,VOJINOVIC S,ARACKI-TRENKIC A,et al. Imagining characteristic of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy[J]. Bosn J Basic Med Sci,2015,15(1):1
[4] ZHU YY,WANG J,WU YB,et al. Two novel mutations in NOTCH3 gene causes cerebral autosomal dominant arteriopathy with subcritical infarct and leucoencephalopathy in two Chinese families[J]. Int J Clin Exp Pathol,2015,8(2):1321
[5]王蓓蓓,石正洪.常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病诊断的研究进展[J].中国全科医学,2015,18(30):3736
[6] SINGHAL S,RICH P,MARKUS HS. The spatial disrtibution of MR imaging abnormalities in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and their relationship to age and clinical features[J]. AJNR Am J Neuroradiol,2005,26(10):2481
[7] AUER DP,PTZ B,GSSL C,et al. Differential lesion patterns in CADASIL and sporadic subcortical arterio sclerotic encephalopathy:MR imaging study with statistical parametrical group comparison[J]. Radiology,2001,218(2):443
[8] LEE YC,LIU CS,CHANG MH,et al. Population-specific spectrum of NOTCH3 mutations,MRI features and founder effect of CADASIL in Chinese[J]. J Neurol,2009,256(2):249
[9]梁静静,卢祖能.伴有皮质下梗死和白质脑病的常染色体显性遗传脑动脉病和Notch3基因突变的亚洲研究现况[J].中风与神经疾病杂志,2017,34(8):756
[10]王兴邦,李娜,赵新静,等.伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病NOTCH3基因突变的研究(附1家系报告)[J].临床神经病学杂志,2015,28(5):341
[11]CAPPELLI A,RAGNO M,CACCCHIO G,et al. High recurrence of the R1006C NOTCH3 mutation in central autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL)[J]. Neurosci Lett,2009,462(2):176
[12]WANG Z,YUAN Y,ZHANG W,et al. NOTCH3 mutations and clinical features in 33 mainland Chinese families with CADASIL[J]. J Neurol Neurosurg Psychiatry,2011,82(5):534
[13]GE W,KUANG HZ,WEI B,et al. A novel cysteine-sparing NOTCH3 mutation in a Chinese family with CADASIL[J].PLo S One,2014,9(8):e104533
[2] CHOUDHARY S,MCL EM,TORCHIA D,et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL)[J]. J Clin Aesthet Dermatol,2013,6(3):29
[3] STOGANOV D,VOJINOVIC S,ARACKI-TRENKIC A,et al. Imagining characteristic of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy[J]. Bosn J Basic Med Sci,2015,15(1):1
[4] ZHU YY,WANG J,WU YB,et al. Two novel mutations in NOTCH3 gene causes cerebral autosomal dominant arteriopathy with subcritical infarct and leucoencephalopathy in two Chinese families[J]. Int J Clin Exp Pathol,2015,8(2):1321
[5]王蓓蓓,石正洪.常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病诊断的研究进展[J].中国全科医学,2015,18(30):3736
[6] SINGHAL S,RICH P,MARKUS HS. The spatial disrtibution of MR imaging abnormalities in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and their relationship to age and clinical features[J]. AJNR Am J Neuroradiol,2005,26(10):2481
[7] AUER DP,PTZ B,GSSL C,et al. Differential lesion patterns in CADASIL and sporadic subcortical arterio sclerotic encephalopathy:MR imaging study with statistical parametrical group comparison[J]. Radiology,2001,218(2):443
[8] LEE YC,LIU CS,CHANG MH,et al. Population-specific spectrum of NOTCH3 mutations,MRI features and founder effect of CADASIL in Chinese[J]. J Neurol,2009,256(2):249
[9]梁静静,卢祖能.伴有皮质下梗死和白质脑病的常染色体显性遗传脑动脉病和Notch3基因突变的亚洲研究现况[J].中风与神经疾病杂志,2017,34(8):756
[10]王兴邦,李娜,赵新静,等.伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病NOTCH3基因突变的研究(附1家系报告)[J].临床神经病学杂志,2015,28(5):341
[11]CAPPELLI A,RAGNO M,CACCCHIO G,et al. High recurrence of the R1006C NOTCH3 mutation in central autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL)[J]. Neurosci Lett,2009,462(2):176
[12]WANG Z,YUAN Y,ZHANG W,et al. NOTCH3 mutations and clinical features in 33 mainland Chinese families with CADASIL[J]. J Neurol Neurosurg Psychiatry,2011,82(5):534
[13]GE W,KUANG HZ,WEI B,et al. A novel cysteine-sparing NOTCH3 mutation in a Chinese family with CADASIL[J].PLo S One,2014,9(8):e104533