Collection and Predictor of ATP1A3 variants

ATP1A3 (Entrez Gene ID: 478; Uniprot ID: AT1A3_HUMAN) encodes a protein belonging to the family of P-type cation transport ATPases, and to the subfamily of Na+/K+-ATPases. It's been proved to be a causal gene for rapid-onset dystonia parkinsonism (RDP; MIM: 128235) and alternating hemiplegia of childhood (AHC; MIM: 614820). This website gathers all reported RDP or AHC patients who have been screening on ATP1A3 gene, as well as our own patients. Moreover this website provides a precise predictor for each missense in ATP1A3 on whether it is functional or not.

Reference: Yang XL, Gao H, Zhang J, Xu XJ, Liu XY, Wu XR, L Wei, YH Zhang, ATP1A3 mutations and genotype-phenotype correlation of alternating hemiplegia of childhood in Chinese patients. 2014. PLoS ONE, 2014;9(5):e97274.

The sequencing data and variant calling results had been distributed to dbGaP. You can apply for it at here.

Atp1α3 is the alpha subunit of an integral membrane protein responsible for maintaining the sodium and potassium concentration gradients. It has two structural conformations, E1 and E2 that selectively bind three Na+ and two K+ respectively. The E2 strucutre of its homologous protein (Atp1α1 from pig renal; identity 86.2% and similarity 93.2%) has been resolved at 2007, and E1 structure been resolved at 2013. The protein crystal structures show that ion binding sites locate inside transmembrane helixes M4~M8.

RDP and AHC both are rare, autosomal dominant, neurological disorder, and mainly caused by mutations in ATP1A3. Though they share some common traits, there still is a considerable list of different characteristics. Following table shows clinical synopses of each disease. (Collected from OMIM)

CATEGORYSUBCATEGORYFEATURES of AHCFEATURES of RDP
Head and NeckEyesAbnormal extraocular movements-
Face-
  • Facial dystonia
  • Hypomimic face
Neck-Torticollis
NeurologicCentral Nervous System
  • Hemiplegia, episodic
  • Quadriplegia, episodic
  • Developmental delay
  • Cognitive decline, progressive
  • Dystonia
  • Choreoathetosis
  • Ataxia
  • Autonomic involvement
  • Seizures
  • Interictal neurologic impairment
  • Dystonia
  • Bulbar and upper limb symptoms more severe than lower limb symptoms
  • Parkinsonism
  • Rapid initial onset of symptoms (hours to weeks)
  • Bradykinesia
  • Slow gait
  • Unsteady gait
  • Postural instability
  • Dysphagia
  • Dysarthria
  • Drooling
  • Mutism
  • Onset may be triggered by emotional stress, fever, exercise, exposure to heat
  • Symptoms stabilize within 4 weeks
  • Most patients remain stable or improve in years after the abrupt onset of symptoms
  • Transient mild dystonia may precede abrupt onset of disorder by several years
  • Normal brain MRI or CT scan
  • Cerebrospinal fluid may show decreased levels of homovanillic acid (HVA)
Behavioral Psychiatric Manifestations-
  • Depression
  • Emotional lability
  • Anxiety
Miscellaneous-
  • Onset mostly before 18 months of age
  • Most cases due to de novo mutation
  • Onset usually in late adolescence or early adulthood (range 15 to 45 years)
  • Childhood onset rarely occurs
  • Treatment with levodopa is not effective
  • Reduced penetrance

The following image demonstrates the locations of ATP1A3 variants on protein domains. The color of the line represents distance to metal ion binding sites, as the upper left panel showed. The dots represent variants with the colors indicating phenotype categories, as the upper right legend showed.

The following table collects almost all reported variants in ATP1A3 from patients. Last update @ 2016/5/8

Or, lot of variant positions:


Highlight group of mutations to verify the accurary of the predictor: