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However, the recent documentation of abnormal elevation of<jats:italic>FMR1<\/jats:italic>mRNA, discovery of fragile X\u2010associated tremor\/ataxia syndrome (FXTAS), and reports of psychiatric disorders in children and adults with the premutation have suggested a pathogenic gene\u2013brain\u2013behavior mechanism. In a large collaborative study, 68 men and 144 women with the<jats:italic>FMR1<\/jats:italic>premutation completed a psychological symptoms checklist and<jats:italic>FMR1<\/jats:italic>genetic testing, including determination of CGG repeat size, percentage of<jats:italic>FMR1<\/jats:italic>protein (FMRP)\u2010positive lymphocytes, and<jats:italic>FMR1<\/jats:italic>mRNA levels. Relative to published norms, men and women with FXTAS symptoms reported higher levels of several types of psychological symptoms. In addition, men and women with the premutation and no overt evidence of FXTAS reported higher levels of obsessive\u2010compulsive symptoms. Elevated<jats:italic>FMR1<\/jats:italic>mRNA, but not CGG repeat size or reduced FMRP (as measured by immunocytochemistry), was significantly associated with increased psychological symptoms, predominantly obsessive\u2010compulsive symptoms and psychoticism, in premutation men with and without FXTAS symptoms. There was no relationship between CGG repeat size,<jats:italic>FMR1<\/jats:italic>mRNA or FMRP and psychological symptoms in premutation women unless the sample was restricted to those with skewed X\u2010activation ratio toward &gt;50% active premutation alleles. The results of this study support the hypothesis that<jats:italic>FMR1<\/jats:italic>function is associated with psychological difficulties in individuals with the premutation, and provide evidence concordant with an RNA toxic gain\u2010of\u2010function model in a neuropsychiatric phenotype. \u00a9 2005 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ajmg.b.30241","type":"journal-article","created":{"date-parts":[[2005,9,23]],"date-time":"2005-09-23T21:53:00Z","timestamp":1127512380000},"page":"115-121","source":"Crossref","is-referenced-by-count":186,"title":["Abnormal elevation of<i>FMR1<\/i>mRNA is associated with psychological symptoms in individuals with the fragile X premutation"],"prefix":"10.1002","volume":"139B","author":[{"given":"David","family":"Hessl","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flora","family":"Tassone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danuta Z.","family":"Loesch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Berry\u2010Kravis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maureen A.","family":"Leehey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise W.","family":"Gane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Barbato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathlin","family":"Rice","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Gould","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah A.","family":"Hall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Grigsby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob A.","family":"Wegelin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Harris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Foster","family":"Lewin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dahlia","family":"Weinberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J.","family":"Hagerman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randi J.","family":"Hagerman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2005,9,23]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0693-147"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19990402)83:4<322::AID-AJMG17>3.0.CO;2-B"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.b.20030"},{"key":"e_1_2_6_5_1","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: A practical and powerful approach to multiple testing","volume":"57","author":"Benjamini Y","year":"1995","journal-title":"J R Stat Soc"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10522"},{"key":"e_1_2_6_7_1","unstructured":"BorghgraefM SteyaertJ DerooS MaesB FrynsJP.2004.Preliminary findings in boys with fragile X premutation: Is there a distinct behavioral phenotype? 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