{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:00:35Z","timestamp":1791306035007,"version":"4.3.1"},"reference-count":24,"publisher":"National Academy of Sciences","issue":"13","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,3,29]]},"abstract":"<jats:p>\n                    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 aneurysms 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 intrauterine growth restriction, infantile hypotonia, and irritability, followed by failure to thrive and short stature. Acrocyanosis, Raynaud\u2019s 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-\u03b1 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\u20132A &gt; G, in the\n                    <jats:italic>SAMHD1<\/jats:italic>\n                    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. Immunoblotting 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\n                    <jats:italic>SAMHD1<\/jats:italic>\n                    mutation indicate its important roles in immunoregulation and cerebral vascular hemeostasis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1014265108","type":"journal-article","created":{"date-parts":[[2011,3,15]],"date-time":"2011-03-15T16:49:42Z","timestamp":1300207782000},"page":"5372-5377","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":113,"title":["Homozygous mutation in\n                    <i>SAMHD1<\/i>\n                    gene causes cerebral vasculopathy and early onset stroke"],"prefix":"10.1073","volume":"108","author":[{"given":"Baozhong","family":"Xin","sequence":"first","affiliation":[{"name":"DDC Clinic for Special Needs Children, Middlefield, OH 44062;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Radiology, Cleveland Clinic, Cleveland, OH 44195;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik G.","family":"Puffenberger","sequence":"additional","affiliation":[{"name":"The Clinic for Special Children, Strasburg, PA 17579;"},{"name":"Department of Biology, Franklin and Marshall College, Lancaster, PA 17603;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claas","family":"Hinze","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Bright","sequence":"additional","affiliation":[{"name":"DDC Clinic for Special Needs Children, Middlefield, OH 44062;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Cleveland State University, Cleveland, OH 44115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aimin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Cleveland State University, Cleveland, OH 44115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guiyun","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Radiology, Cleveland Clinic, Cleveland, OH 44195;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jilda","family":"Vargus-Adams","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitris","family":"Agamanolis","sequence":"additional","affiliation":[{"name":"Department of Pathology, Akron Children\u2019s Hospital, OH 44308;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Wang","sequence":"additional","affiliation":[{"name":"DDC Clinic for Special Needs Children, Middlefield, OH 44062;"},{"name":"Department of Pediatrics, Rainbow Babies and Children\u2019s Hospital, Cleveland, OH 44106; and"},{"name":"Department of Molecular Cardiology, Cleveland Clinic, Cleveland, OH 44195"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2011,3,14]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1136\/adc.2008.142836"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1097\/MOP.0b013e3282f1883b"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1136\/pgmj.2007.060319"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/pro.5560060128"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2003.11.001"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0004(98)01293-6"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.373"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8749.2010.03727.x"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-2478(00)00276-5"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01936-06"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.20.12893-12904.2005"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1186\/1743-422X-5-114"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.200700954"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1097\/00041433-200110000-00011"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra022694"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.22.012703.104644"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.107.161653"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1361.075"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.108.789172"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.185777"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra0804622"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0b013e32831cf5e6"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0401194101"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0908457107"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1014265108","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T19:51:30Z","timestamp":1649793090000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1014265108"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,3,14]]},"references-count":24,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2011,3,29]]}},"alternative-id":["10.1073\/pnas.1014265108"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1014265108","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,3,14]]},"assertion":[{"value":"2011-03-14","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}