Identification of ATP1A3 Mutations by Exome Sequencing as the Cause of Alternating Hemiplegia of Childhood in Japanese Patients

PLOS ONE, Dec 2019

Background Alternating hemiplegia of childhood (AHC) is a rare disorder characterized by transient repeated attacks of paresis and cognitive impairment. Recent studies from the U.S. and Europe have described ATP1A3 mutations in AHC. However, the genotype-phenotype relationship remains unclear. The purpose of this study was to identify the genetic abnormality in a Japanese cohort of AHC using exome analysis. Principal Findings A total of 712,558 genetic single nucleotide variations in 8 patients with sporadic AHC were found. After a series of exclusions, mutations of three genes were regarded as candidate causes of AHC. Each patient harbored a heterozygous missense mutation of ATP1A3, which included G755C, E815K, C927Y and D801N. All mutations were at highly conserved amino acid residues and deduced to affect ATPase activity of the corresponding ATP pump, the product of ATP1A3. They were de novo mutations and not identified in 96 healthy volunteers. Using Sanger sequencing, E815K was found in two other sporadic cases of AHC. In this study, E815K was found in 5 of 10 patients (50%), a prevalence higher than that reported in two recent studies [19 of 82 (23%) and 7 of 24 (29%)]. Furthermore, the clinical data of the affected individuals indicated that E815K resulted in a severer phenotype compared with other ATP1A3 mutations. Interpretation Heterozygous de novo mutations of ATP1A3 were identified in all Japanese patients with AHC examined in this study, confirming that ATP1A3 mutation is the cause of AHC.

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Identification of ATP1A3 Mutations by Exome Sequencing as the Cause of Alternating Hemiplegia of Childhood in Japanese Patients

et al. (2013) Identification of ATP1A3 Mutations by Exome Sequencing as the Cause of Alternating Hemiplegia of Childhood in Japanese Patients. PLoS ONE 8(2): e56120. doi:10.1371/journal.pone.0056120 Identification of ATP1A3 Mutations by Exome Sequencing as the Cause of Alternating Hemiplegia of Childhood in Japanese Patients Atsushi Ishii 0 Yoshiaki Saito 0 Jun Mitsui 0 Hiroyuki Ishiura 0 Jun Yoshimura 0 Hidee Arai 0 Sumimasa Yamashita 0 Sadami Kimura 0 Hirokazu Oguni 0 Shinichi Morishita 0 Shoji Tsuji 0 Masayuki Sasaki 0 Shinichi Hirose 0 Matthaios Speletas, University of Thessaly, Greece 0 1 Department of Pediatrics, School of Medicine, Fukuoka University , Fukuoka , Japan , 2 Central Research Institute for the Molecular Pathomechanisms of Epilepsy, Fukuoka University , Fukuoka , Japan , 3 Department of Child Neurology, National Center of Neurology and Psychiatry, Kodaira, Japan, 4 Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, 5 Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan, 6 Department of Neurology, Chiba Children's Hospital , Chiba , Japan , 7 Division of Child Neurology, Kanagawa Children's Medical Center , Yokohama , Japan , 8 Division of Child Neurology, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Japan, 9 Department of Pediatrics, Tokyo Women's Medical University , Tokyo , Japan Background: Alternating hemiplegia of childhood (AHC) is a rare disorder characterized by transient repeated attacks of paresis and cognitive impairment. Recent studies from the U.S. and Europe have described ATP1A3 mutations in AHC. However, the genotype-phenotype relationship remains unclear. The purpose of this study was to identify the genetic abnormality in a Japanese cohort of AHC using exome analysis. Principal Findings: A total of 712,558 genetic single nucleotide variations in 8 patients with sporadic AHC were found. After a series of exclusions, mutations of three genes were regarded as candidate causes of AHC. Each patient harbored a heterozygous missense mutation of ATP1A3, which included G755C, E815K, C927Y and D801N. All mutations were at highly conserved amino acid residues and deduced to affect ATPase activity of the corresponding ATP pump, the product of ATP1A3. They were de novo mutations and not identified in 96 healthy volunteers. Using Sanger sequencing, E815K was found in two other sporadic cases of AHC. In this study, E815K was found in 5 of 10 patients (50%), a prevalence higher than that reported in two recent studies [19 of 82 (23%) and 7 of 24 (29%)]. Furthermore, the clinical data of the affected individuals indicated that E815K resulted in a severer phenotype compared with other ATP1A3 mutations. Interpretation: Heterozygous de novo mutations of ATP1A3 were identified in all Japanese patients with AHC examined in this study, confirming that ATP1A3 mutation is the cause of AHC. - Competing Interests: The authors have declared that no competing interests exist. Alternating hemiplegia of childhood (AHC) (MIM 104290) is a rare disorder characterized by transient repeated attacks of paresis on either one or both sides of the body, occulomotor and autonomic abnormalities, movement disorders, and cognitive impairment [1,2]. AHC is predominantly observed in sporadic cases without familial history, although familial AHC with autosomal dominant inheritance has also been reported [3]. Only about 50 patients with sporadic AHC have been reported in Japan and the estimated prevalence of AHC is one in a million births [4]. Since the clinical features of AHC share similarity with those of familial hemiplegic migraine (FHM), previous studies applied mutational analyses of CACNA1A (NM_000068) and ATP1A2 (MN_000702), which are responsible for two types of FHM, FHM1 (MIM 601011) [5] and FHM2 (MIM 182340) [6,7], respectively, to explore the genetic cause of AHC. Although T378N, a mutation of ATP1A2, was identified in four affected members of a Greek family with familial AHC [3], mutations of ATP1A2 have neither been observed in other familial cases nor in sporadic cases of AHC. Thus, candidate gene approaches have been unsuccessful in identifying the molecular pathogenic mechanism of AHC. To elucidate the molecular basis of AHC, we hypothesized that sporadic AHC is caused by de novo mutations among novel nonsynonymous coding variants, which are shared in patients with AHC. To test this hypothesis, we built a de novo mutation detection pipeline using the exome sequencing method (Figure 1). Using this technique, we found that de novo mutations of ATP1A3 (NM_152296) cause sporadic AHC. A total of 712,558 genetic single nucleotide variations (SNVs) and 141,933 small indels were found, including previously known and synonymous genomic variations (Table 1). The ratios of nonoverlapping variations in these patients are comparable to those of Asian or Japanese pop (...truncated)


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Atsushi Ishii, Yoshiaki Saito, Jun Mitsui, Hiroyuki Ishiura, Jun Yoshimura, Hidee Arai, Sumimasa Yamashita, Sadami Kimura, Hirokazu Oguni, Shinichi Morishita, Shoji Tsuji, Masayuki Sasaki, Shinichi Hirose. Identification of ATP1A3 Mutations by Exome Sequencing as the Cause of Alternating Hemiplegia of Childhood in Japanese Patients, PLOS ONE, 2013, Volume 8, Issue 2, DOI: 10.1371/journal.pone.0056120