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
Plateforme GENOMAX, Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
Mov Disord. 2015 Mar;30(3):423-7. doi: 10.1002/mds.26115. Epub 2014 Dec 27.
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.
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.
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.
除亨廷顿舞蹈病外，对于与肌张力障碍相关的常染色体显性遗传性舞蹈病的遗传学知之甚少。在此，我们确定腺苷酸环化酶5（ADCY5）是早发性舞蹈病和肌张力障碍一个可能的新致病基因。
对一个患有与肌张力障碍相关的常染色体显性遗传性舞蹈病的三代家庭进行全外显子组测序，在ADCY5基因5'供体剪接位点发现一个新生突变——c.2088 + 1G>A，该突变与疾病共分离。此突变似乎导致RNA不稳定，进而导致ADCY5单倍体不足。
我们的发现证实了该疾病的遗传/临床异质性；此前在一个患有运动障碍-面部肌纤维颤搐的家庭以及两个散发性发作性舞蹈病/肌张力障碍-面部肌纤维颤搐的无关病例中发现了ADCY5突变，同时ADCY5在纹状体中高表达以及ADCY5基因缺陷小鼠出现运动障碍，这些均佐证了我们的发现。因此，ADCY5基因分析可能有助于不明原因的早发性运动亢进性疾病的诊断检查。
