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2023 ACMG Annual Clinical Genetics Meeting Digital ...
Electrophysiological functional studies of an
...
Electrophysiological functional studies of an
ATP1A3
variant in an individual with a relatively mild neurological phenotype reveal loss of function
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Pdf Summary
The summary of the document is as follows:<br /><br />This case report discusses a 4-year-old boy with intermittent episodes of weakness and encephalopathy. He also experiences speech regression, hand tremors, and fevers associated with pain. Genetic testing revealed a de novo ATP1A3 variant, which is believed to be the cause of the boy's symptoms. The researchers conducted electrophysiological functional studies on the variant and found that it leads to a loss of function. Despite the loss of ion transport activity, the variant still appears to fold and reach the cell surface. The researchers applied ACMG criteria and classified the variant as likely pathogenic. They performed experiments on human ATP1A3 RNA expressed in Xenopus oocytes and found that the variant does not produce steady-state currents like the wildtype, indicating its loss-of-function impact. They also demonstrated that the variant reaches the cell surface, similar to the wildtype protein. Furthermore, the variant disrupts extracellular sodium binding/unbinding and demonstrates extremely small transient currents compared to the wildtype. The study expands the understanding of ATP1A3-associated diseases, which are characterized by neurological phenotypes. The wide range of phenotypic variability in these diseases includes symptoms such as encephalopathy, weakness, and ataxia. The case report describes a phenotype similar to febrile encephalopathy/weakness but not triggered by fever.
Asset Subtitle
Presenting Author - Chetan Immanneni, BA; Co-Author - Song Jiao, PhD; Co-Author - Daniel Calame, MD PhD; Co-Author - Lisa T. Emrick, MD; Co-Author - Miguel Holmgren, PhD; Co-Author - Sho T. Yano, MD, PhD;
Meta Tag
Brain/Nervous System
Delineation of Diseases
Genotype-Phenotype Correlations
Molecular Pathophysiology
Co-Author
Song Jiao, PhD
Co-Author
Daniel Calame, MD PhD
Co-Author
Lisa T. Emrick, MD
Co-Author
Miguel Holmgren, PhD
Co-Author
Sho T. Yano, MD, PhD
Presenting Author
Chetan Immanneni, BA
Keywords
4-year-old boy
weakness
encephalopathy
speech regression
hand tremors
ATP1A3 variant
genetic testing
ion transport activity
cell surface
neurological phenotypes
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