Gain-of-Function ADCY5 Mutations in Familial Dyskinesia with Facial Myokymia

被引:103
作者
Chen, Ying-Zhang [1 ]
Friedman, Jennifer R. [2 ,3 ]
Chen, Dong-Hui [4 ]
Chan, Guy C. -K. [5 ]
Bloss, Cinnamon S. [6 ,7 ]
Hisama, Fuki M. [1 ]
Topol, Sarah E. [6 ,7 ]
Carson, Andrew R. [6 ,7 ]
Pham, Phillip H. [6 ,7 ]
Bonkowski, Emily S. [4 ]
Scott, Erick R. [6 ,7 ]
Lee, Janel K. [6 ,7 ]
Zhang, Guangfa [6 ,7 ]
Oliveira, Glenn [6 ,7 ]
Xu, Jian [8 ]
Scott-Van Zeeland, Ashley A. [6 ,7 ]
Chen, Qi [9 ]
Levy, Samuel [6 ,7 ]
Topol, Eric J. [6 ,7 ]
Storm, Daniel [5 ]
Swanson, Phillip D. [4 ]
Bird, Thomas D. [4 ,10 ]
Schork, Nicholas J. [6 ,7 ]
Raskind, Wendy H. [1 ,10 ,11 ,12 ]
Torkamani, Ali [6 ,7 ]
机构
[1] Univ Washington, Dept Med Med Genet, Seattle, WA 98195 USA
[2] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA
[3] Univ Calif San Diego, Dept Pediat, San Diego, CA 92103 USA
[4] Univ Washington, Dept Neurol, Seattle, WA 98195 USA
[5] Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA
[6] Scripps Hlth, Scripps Translat Sci Inst, San Diego, CA USA
[7] Scripps Res Inst, San Diego, CA USA
[8] Northwestern Univ, Dept Physiol, Chicago, IL 60611 USA
[9] Fujian Normal Univ, Southern Biomed Res Ctr, Fuzhou, Peoples R China
[10] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA
[11] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA
[12] Mental Illness Res Educ & Clin Ctr, Seattle, WA USA
关键词
ADENYLYL-CYCLASE; FDFM;
D O I
10.1002/ana.24119
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
ObjectiveTo 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). MethodsWhole 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. ResultsThe 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 -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. InterpretationFDFM is likely caused by gain-of-function mutations in different domains of ADCY5the 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
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收藏
页码:542 / 549
页数:8
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