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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Homozygous mutation in SAMHD1 gene causes cerebral vasculopathy and early onset stroke
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Homozygous mutation in SAMHD1 gene causes cerebral vasculopathy and early onset stroke

机译：SAMHD1基因的纯合突变导致脑血管病变和中风早期发作

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摘要

We describe an autosomal recessive condition characterized with cerebral vasculopathy and early onset of stroke in 14 individuals in Old Order Amish. The phenotype of the condition was highly heterogeneous, ranging from severe developmental disability to normal schooling. Cerebral vasculopathy was a major hallmark of the condition with a common theme of multifocal stenoses and aneur-ysms in large arteries, accompanied by chronic ischemic changes, moyamoya morphology, and evidence of prior acute infarction and hemorrhage. Early signs of the disease included mild intra-uterine growth restriction, infantile hypotonia, and irritability, followed by failure to thrive and short stature. Acrocyanosis, Raynaud's phenomenon, chilblain lesions, low-pitch hoarse voice, glaucoma, migraine headache, and arthritis were frequently observed. The early onset or recurrence of strokes secondary to cerebral vasculopathy seems to always be associated with poor outcomes. The elevated erythrocyte sedimentation rate (ESR), IgG, neopterin, and TNF-a found in these patients suggested an immune disorder. Through genomewide homozygosity mapping, we localized the disease gene to chromosome (Chr) 20q11.22-q12. Candidate gene sequencing identified a homozygous mutation, C.1411-2A > G, in the SAMHD1 gene, being associated with this condition. The mutation appeared at the splice-acceptor site of intron 12, resulted in the skipping of exon 13, and gave rise to an aberrant protein with in-frame deletion of 31 amino acids. Im-munoblotting analysis showed lack of mutant SAMHD1 protein expression in affected cell lines. The function of SAMHD1 remains unclear, but the inflammatory vasculopathies of the brain found in the patients with SAMHD1 mutation indicate its important roles in immunoregulation and cerebral vascular hemeostasis.
机译：我们描述了以老年性阿米什人中的14个人为特征的常染色体隐性遗传病，其特征为脑血管病变和中风的早期发作。该病的表型高度异质，从严重的发育障碍到正常的上学不等。脑血管病是该疾病的主要标志，其常见主题是大动脉多灶性狭窄和动脉瘤，伴有慢性缺血性变化，烟雾病形态以及先前急性梗塞和出血的证据。该病的早期体征包括子宫内轻度生长受限，婴儿肌张力低下和易怒，其次是failure壮成长和身材矮小。经常观察到肢端肥大症，雷诺现象，冻疮病变，低音嘶哑的声音，青光眼，偏头痛和关节炎。脑血管病继发的中风的早期发作或复发似乎总是与不良预后相关。在这些患者中发现的红细胞沉降率（ESR），IgG，新蝶呤和TNF-a升高提示存在免疫性疾病。通过全基因组纯合性作图，我们将该病基因定位于染色体（Chr）20q11.22-q12。候选基因测序确定了SAMHD1基因中的纯合突变，即C.1411-2A> G，与这种情况有关。该突变出现在内含子12的剪接受体位点，导致外显子13的跳过，并产生了异常的蛋白质，其框内缺失了31个氨基酸。免疫印迹分析显示受影响的细胞系中缺少突变的SAMHD1蛋白表达。 SAMHD1的功能尚不清楚，但在具有SAMHD1突变的患者中发现的脑部炎性血管病变表明其在免疫调节和脑血管血肿中的重要作用。

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  • 作者

    Baozhong Xin; Stephen Jones; Erik G. Puffenberger; Claas Hinze; Alicia Bright; Haiyan Tan; Aimin Zhou; Guiyun Wu; Jilda Vargus-Adams; Dimitris Agamanolis; Heng Wang;

  • 作者单位

    DDC Clinic for Special Needs Children, Middlefield, OH 44062;

    Department of Radiology, Cleveland Clinic, Cleveland, OH 44195;

    The Clinic for Special Children, Strasburg, PA 17579,Department of Biology, Franklin and Marshall College, Lancaster, PA 17603;

    Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;

    DDC Clinic for Special Needs Children, Middlefield, OH 44062;

    Department of Chemistry, Cleveland State University, Cleveland, OH 44115;

    Department of Chemistry, Cleveland State University, Cleveland, OH 44115;

    Department of Radiology, Cleveland Clinic, Cleveland, OH 44195;

    Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;

    Department of Pathology, Akron Children's Hospital, OH 44308;

    DDC Clinic for Special Needs Children, Middlefield, OH 44062,Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland, OH 44106,Department of MolecularCardiology, Cleveland Clinic, Cleveland, OH 44195;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    genotyping; snp arrays; autozygosity;

    机译：基因分型;snp阵列;自合子;

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