{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T11:51:33Z","timestamp":1791201093654,"version":"4.2.0"},"reference-count":27,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2014,3,13]],"date-time":"2014-03-13T00:00:00Z","timestamp":1394668800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2014,4]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To identify the cause of childhood onset involuntary paroxysmal choreiform and dystonic movements in 2 unrelated sporadic cases and to investigate the functional effect of missense mutations in adenylyl cyclase 5 (<jats:italic>ADCY5<\/jats:italic>) in sporadic and inherited cases of autosomal dominant familial dyskinesia with facial myokymia (FDFM).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Whole exome sequencing was performed on 2 parent\u2013child trios. The effect of mutations in <jats:italic>ADCY5<\/jats:italic> was studied by measurement of cyclic adenosine monophosphate (cAMP) accumulation under stimulatory and inhibitory conditions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The same de novo mutation (c.1252C&gt;T, p.R418W) in <jats:italic>ADCY5<\/jats:italic> was found in both studied cases. An inherited missense mutation (c.2176G&gt;A, p.A726T) in <jats:italic>ADCY5<\/jats:italic> was previously reported in a family with FDFM. The significant phenotypic overlap with FDFM was recognized in both cases only after discovery of the molecular link. The inherited mutation in the FDFM family and the recurrent de novo mutation affect residues in different protein domains, the first cytoplasmic domain and the first membrane\u2010spanning domain, respectively. Functional studies revealed a statistically significant increase in \u03b2\u2010receptor agonist\u2010stimulated intracellular cAMP consistent with an increase in adenylyl cyclase activity for both mutants relative to wild\u2010type protein, indicative of a gain\u2010of\u2010function effect.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>FDFM is likely caused by gain\u2010of\u2010function mutations in different domains of ADCY5\u2014the first definitive link between adenylyl cyclase mutation and human disease. We have illustrated the power of hypothesis\u2010free exome sequencing in establishing diagnoses in rare disorders with complex and variable phenotype. Mutations in <jats:italic>ADCY5<\/jats:italic> should be considered in patients with undiagnosed complex movement disorders even in the absence of a family history. Ann Neurol 2014;75:542\u2013549<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.24119","type":"journal-article","created":{"date-parts":[[2014,2,17]],"date-time":"2014-02-17T11:03:02Z","timestamp":1392634982000},"page":"542-549","source":"Crossref","is-referenced-by-count":123,"title":["Gain\u2010of\u2010function <i>ADCY5<\/i> mutations in familial dyskinesia with facial myokymia"],"prefix":"10.1002","volume":"75","author":[{"given":"Ying\u2010Zhang","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Medicine\/Medical Genetics University of Washington Seattle WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer R.","family":"Friedman","sequence":"additional","affiliation":[{"name":"Departments of Neurosciences and Pediatrics University of California, San Diego San Diego CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong\u2010Hui","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology 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