A de novo ADCY5 mutation causes early-onset autosomal dominant chorea and dystonia

• Published in: Movement disorders Vol. 30; no. 3; pp. 423 - 427
• Main Authors: Carapito, Raphael, Paul, Nicodème, Untrau, Meiggie, Le Gentil, Marion, Ott, Louise, Alsaleh, Ghada, Jochem, Pierre, Radosavljevic, Mirjana, Le Caignec, Cédric, David, Albert, Damier, Philippe, Isidor, Bertrand, Bahram, Seiamak
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.03.2015; Wiley Subscription Services, Inc
• Subjects: ADCY5; Adenylyl Cyclases - genetics; Adolescent; Adult; Chorea - genetics; chorea associated with dystonia; DNA Mutational Analysis; Dystonic Disorders - genetics; exome; Family Health; Female; Humans; Male; Movement disorders; Mutation - genetics; exome; chorea associated with dystonia; ADCY5
• ISSN: 0885-3185; 1531-8257
• DOI: 10.1002/mds.26115

ABSTRACT Importance Apart from Huntington's disease, little is known of the genetics of autosomal dominant chorea associated with dystonia. Here we identify adenylate cyclase 5 (ADCY5) as a likely new causal gene for early‐onset chorea and dystonia. Observations Whole exome sequencing in a three‐generation family affected with autosomal dominant chorea associated with dystonia identified a single de novo mutation—c.2088+1G>A in a 5' donor splice‐site of ADCY5—segregating with the disease. This mutation seeming leads to RNA instability and therefore ADCY5 haploinsufficiency. Conclusions and Relevance Our finding confirms the genetic/clinical heterogeneity of the disorder; corroborated by previous identification of ADCY5 mutations in one family with dyskinesia‐facial myokymia and in two unrelated sporadic cases of paxoysmal choreic/dystonia‐facial myokymia; ADCY5's high expression in the striatum and movement disorders in ADCY5‐deficient mice. Hence ADCY5 genetic analyses may be relevant in the diagnostic workup of unexplained early‐onset hyperkinetic movement disorders. © 2014 International Parkinson and Movement Disorder Society