Gain-of-function ADCY5 mutations in familial dyskinesia with facial myokymia
Ying-Zhang Chen MD, PhD
Department of Medicine/Medical Genetics, University of Washington, Seattle, WA
Search for more papers by this authorJennifer R. Friedman MD
Departments of Neurosciences and Pediatrics, University of California, San Diego, San Diego, CA
Search for more papers by this authorDong-Hui Chen MD, PhD
Department of Neurology, University of Washington, Seattle, WA
Search for more papers by this authorGuy C.-K. Chan PhD
Department of Pharmacology, University of Washington, Seattle, WA
Search for more papers by this authorCinnamon S. Bloss PhD
Scripps Translational Science Institute, Scripps Health, and Scripps Research Institute, San Diego, CA
Search for more papers by this authorFuki M. Hisama MD
Department of Medicine/Medical Genetics, University of Washington, Seattle, WA
Search for more papers by this authorSarah E. Topol RN
Scripps Translational Science Institute, Scripps Health, and Scripps Research Institute, San Diego, CA
Search for more papers by this authorAndrew R. Carson PhD
Scripps Translational Science Institute, Scripps Health, and Scripps Research Institute, San Diego, CA
Search for more papers by this authorPhillip H. Pham BS
Scripps Translational Science Institute, Scripps Health, and Scripps Research Institute, San Diego, CA
Search for more papers by this authorEmily S. Bonkowski BS
Department of Neurology, University of Washington, Seattle, WA
Search for more papers by this authorErick R. Scott MD
Scripps Translational Science Institute, Scripps Health, and Scripps Research Institute, San Diego, CA
Search for more papers by this authorJanel K. Lee BS
Scripps Translational Science Institute, Scripps Health, and Scripps Research Institute, San Diego, CA
Search for more papers by this authorGuangfa Zhang PhD
Scripps Translational Science Institute, Scripps Health, and Scripps Research Institute, San Diego, CA
Search for more papers by this authorGlenn Oliveira BS
Scripps Translational Science Institute, Scripps Health, and Scripps Research Institute, San Diego, CA
Search for more papers by this authorJian Xu PhD
Department of Physiology, Northwestern University, Chicago, IL
Search for more papers by this authorAshley A. Scott-Van Zeeland PhD
Scripps Translational Science Institute, Scripps Health, and Scripps Research Institute, San Diego, CA
Search for more papers by this authorQi Chen PhD
Southern Biomedical Research Center, Fujian Normal University, Fuzhou, China
Search for more papers by this authorSamuel Levy PhD
Scripps Translational Science Institute, Scripps Health, and Scripps Research Institute, San Diego, CA
Search for more papers by this authorEric J. Topol MD
Scripps Translational Science Institute, Scripps Health, and Scripps Research Institute, San Diego, CA
Search for more papers by this authorDaniel Storm PhD
Department of Pharmacology, University of Washington, Seattle, WA
Search for more papers by this authorPhillip D. Swanson MD, PhD
Department of Neurology, University of Washington, Seattle, WA
Search for more papers by this authorThomas D. Bird MD
Department of Neurology, University of Washington, Seattle, WA
Veterans Affairs Puget Sound Health Care System Geriatric Research, Education, and Clinical Center, Seattle, WA
Search for more papers by this authorNicholas J. Schork PhD
Scripps Translational Science Institute, Scripps Health, and Scripps Research Institute, San Diego, CA
Search for more papers by this authorWendy H. Raskind MD, PhD
Veterans Affairs Puget Sound Health Care System Geriatric Research, Education, and Clinical Center, Seattle, WA
Departments of Medicine/Medical Genetics and Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA
Mental Illness Research, Education, and Clinical Center, Seattle, WA
Search for more papers by this authorCorresponding Author
Ali Torkamani PhD
Scripps Translational Science Institute, Scripps Health, and Scripps Research Institute, San Diego, CA
Address correspondence to Dr Torkamani, 3344 North Torrey Pines Court, Ste 300, La Jolla, CA 92037. E-mail: [email protected]Search for more papers by this authorYing-Zhang Chen MD, PhD
Department of Medicine/Medical Genetics, University of Washington, Seattle, WA
Search for more papers by this authorJennifer R. Friedman MD
Departments of Neurosciences and Pediatrics, University of California, San Diego, San Diego, CA
Search for more papers by this authorDong-Hui Chen MD, PhD
Department of Neurology, University of Washington, Seattle, WA
Search for more papers by this authorGuy C.-K. Chan PhD
Department of Pharmacology, University of Washington, Seattle, WA
Search for more papers by this authorCinnamon S. Bloss PhD
Scripps Translational Science Institute, Scripps Health, and Scripps Research Institute, San Diego, CA
Search for more papers by this authorFuki M. Hisama MD
Department of Medicine/Medical Genetics, University of Washington, Seattle, WA
Search for more papers by this authorSarah E. Topol RN
Scripps Translational Science Institute, Scripps Health, and Scripps Research Institute, San Diego, CA
Search for more papers by this authorAndrew R. Carson PhD
Scripps Translational Science Institute, Scripps Health, and Scripps Research Institute, San Diego, CA
Search for more papers by this authorPhillip H. Pham BS
Scripps Translational Science Institute, Scripps Health, and Scripps Research Institute, San Diego, CA
Search for more papers by this authorEmily S. Bonkowski BS
Department of Neurology, University of Washington, Seattle, WA
Search for more papers by this authorErick R. Scott MD
Scripps Translational Science Institute, Scripps Health, and Scripps Research Institute, San Diego, CA
Search for more papers by this authorJanel K. Lee BS
Scripps Translational Science Institute, Scripps Health, and Scripps Research Institute, San Diego, CA
Search for more papers by this authorGuangfa Zhang PhD
Scripps Translational Science Institute, Scripps Health, and Scripps Research Institute, San Diego, CA
Search for more papers by this authorGlenn Oliveira BS
Scripps Translational Science Institute, Scripps Health, and Scripps Research Institute, San Diego, CA
Search for more papers by this authorJian Xu PhD
Department of Physiology, Northwestern University, Chicago, IL
Search for more papers by this authorAshley A. Scott-Van Zeeland PhD
Scripps Translational Science Institute, Scripps Health, and Scripps Research Institute, San Diego, CA
Search for more papers by this authorQi Chen PhD
Southern Biomedical Research Center, Fujian Normal University, Fuzhou, China
Search for more papers by this authorSamuel Levy PhD
Scripps Translational Science Institute, Scripps Health, and Scripps Research Institute, San Diego, CA
Search for more papers by this authorEric J. Topol MD
Scripps Translational Science Institute, Scripps Health, and Scripps Research Institute, San Diego, CA
Search for more papers by this authorDaniel Storm PhD
Department of Pharmacology, University of Washington, Seattle, WA
Search for more papers by this authorPhillip D. Swanson MD, PhD
Department of Neurology, University of Washington, Seattle, WA
Search for more papers by this authorThomas D. Bird MD
Department of Neurology, University of Washington, Seattle, WA
Veterans Affairs Puget Sound Health Care System Geriatric Research, Education, and Clinical Center, Seattle, WA
Search for more papers by this authorNicholas J. Schork PhD
Scripps Translational Science Institute, Scripps Health, and Scripps Research Institute, San Diego, CA
Search for more papers by this authorWendy H. Raskind MD, PhD
Veterans Affairs Puget Sound Health Care System Geriatric Research, Education, and Clinical Center, Seattle, WA
Departments of Medicine/Medical Genetics and Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA
Mental Illness Research, Education, and Clinical Center, Seattle, WA
Search for more papers by this authorCorresponding Author
Ali Torkamani PhD
Scripps Translational Science Institute, Scripps Health, and Scripps Research Institute, San Diego, CA
Address correspondence to Dr Torkamani, 3344 North Torrey Pines Court, Ste 300, La Jolla, CA 92037. E-mail: [email protected]Search for more papers by this authorAbstract
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
Supporting Information
Additional Supporting Information may be found in the online version of this article.
| Filename | Description |
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| ana24119-sup-0001-suppmovie1.mov27.7 MB | Supplementary Information Movie 1. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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