Gain-of-function ADCY5 mutations in familial dyskinesia with facial myokymia

Objective 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 (ADCY5) in sporadic and inherited cases of autosomal dominant familial dyskin...

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Published in:	Annals of neurology Vol. 75; no. 4; pp. 542 - 549
Main Authors:	Chen, Ying-Zhang, Friedman, Jennifer R., Chen, Dong-Hui, Chan, Guy C.-K., Bloss, Cinnamon S., Hisama, Fuki M., Topol, Sarah E., Carson, Andrew R., Pham, Phillip H., Bonkowski, Emily S., Scott, Erick R., Lee, Janel K., Zhang, Guangfa, Oliveira, Glenn, Xu, Jian, Scott-Van Zeeland, Ashley A., Chen, Qi, Levy, Samuel, Topol, Eric J., Storm, Daniel, Swanson, Phillip D., Bird, Thomas D., Schork, Nicholas J., Raskind, Wendy H., Torkamani, Ali
Format:	Journal Article
Language:	English
Published:	United States Blackwell Publishing Ltd 01-04-2014 Wiley Subscription Services, Inc
Subjects:	Adenylyl Cyclases - genetics Adenylyl Cyclases - metabolism Adolescent Cyclic AMP - metabolism Dystonic Disorders - complications Dystonic Disorders - genetics Facial Nerve Diseases - complications Facial Nerve Diseases - genetics Female Green Fluorescent Proteins - genetics HEK293 Cells Humans Medical research Models, Molecular Mutagenesis, Site-Directed Mutation Mutation, Missense - genetics Transfection
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Summary:	Objective 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 (ADCY5) in sporadic and inherited cases of autosomal dominant familial dyskinesia with facial myokymia (FDFM). Methods Whole exome sequencing was performed on 2 parent–child trios. The effect of mutations in ADCY5 was studied by measurement of cyclic adenosine monophosphate (cAMP) accumulation under stimulatory and inhibitory conditions. Results The same de novo mutation (c.1252C>T, p.R418W) in ADCY5 was found in both studied cases. An inherited missense mutation (c.2176G>A, p.A726T) in ADCY5 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‐spanning domain, respectively. Functional studies revealed a statistically significant increase in β‐receptor agonist‐stimulated intracellular cAMP consistent with an increase in adenylyl cyclase activity for both mutants relative to wild‐type protein, indicative of a gain‐of‐function effect. Interpretation FDFM is likely caused by gain‐of‐function mutations in different domains of ADCY5—the first definitive link between adenylyl cyclase mutation and human disease. We have illustrated the power of hypothesis‐free exome sequencing in establishing diagnoses in rare disorders with complex and variable phenotype. Mutations in ADCY5 should be considered in patients with undiagnosed complex movement disorders even in the absence of a family history. Ann Neurol 2014;75:542–549
Bibliography:	ArticleID:ANA24119 ark:/67375/WNG-W2BLRT0G-8 istex:B2A23C79709263BD51DCC915E8E917CEB5F17DB4 ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 Y.-Z.C., J.R.F., D.-H.C., and G.C.-K.C. contributed equally.
ISSN:	0364-5134 1531-8249
DOI:	10.1002/ana.24119