A Distinct Phenotype in a Novel ATP1A3 Mutation: Connecting the Two Ends of a Spectrum.
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ABSTRACT:
SUBMITTER: Pereira P
PROVIDER: S-EPMC6353589 | biostudies-literature | 2016 Jul-Aug
REPOSITORIES: biostudies-literature
Publications
A Distinct Phenotype in a Novel ATP1A3 Mutation: Connecting the Two Ends of a Spectrum.
Pereira Pedro P Guerreiro Andreia A Fonseca Maria M Halpern Cristina C Pinto-Basto Jorge J Monteiro José P JP
Movement disorders clinical practice 20151128 4
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Project description:ObjectivePathogenic mutations of the TRAPPC9 gene are the rare genetic causes of autosomal recessive intellectual disability (ID). There are several features that are not fully penetrant such as microcephaly, dysmorphic facial features, obesity, autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), and brain abnormalities in TRAPPC9 mutations.MethodsWe performed whole-exome sequencing to evaluate 2 Turkish siblings with ASD and ID born to healthy and consanguineous parents. Parental samples were also analyzed, specifically targeting variants detected in these patients.ResultsWe present a novel homozygous mutation in the TRAPPC9 gene, c.484G>T (p.Glu162Ter). Additionally, we aim to provide a more comprehensive understanding of the clinical features of a novel homozygous TRAPPC9 mutation. In addition to ID, the siblings in this report suffered from ASD and specific stereotypes as hand-flapping behavior.ConclusionAlthough there are inconsistencies in the presentation of ASD in TRAPPC9 mutations, repetitive behaviors (hand-flapping) were typical in our cases and several previous reports. The current mutation was described to cause a homozygous premature termination codon that resulted in the absence of the TRAPPC9 protein. We suggest that TRAPPC9 mutations are not only related to ID but also to ASD and hand-flapping behaviors.
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Project description:ObjectiveTo describe a phenotype caused by ATP1A3 mutations, which manifests as dystonia, dysmorphism of the face, encephalopathy with developmental delay, brain MRI abnormalities always including cerebellar hypoplasia, no hemiplegia (Ø) (D-DEMØ), and neonatal onset.MethodsReview and analysis of clinical and genetic data.ResultsPatients shared the above traits and had whole-exome sequencing that showed de novo variants of the ATP1A3 gene, predicted to be disease causing and occurring in regions of the protein critical for pump function. Patient 1 (c.1079C>G, p.Thr360Arg), an 8-year-old girl, presented on day 1 of life with episodic dystonia, complex partial seizures, and facial dysmorphism. MRI of the brain revealed cerebellar hypoplasia. Patient 2 (c.420G>T, p.Gln140His), an 18-year-old man, presented on day 1 of life with hypotonia, tremor, and facial dysmorphism. He later developed dystonia. MRI of the brain revealed cerebellar hypoplasia and, later, further cerebellar volume loss (atrophy). Patient 3 (c.974G>A, Gly325Asp), a 13-year-old girl, presented on day 1 of life with tremor, episodic dystonia, and facial dysmorphism. MRI of the brain showed severe cerebellar hypoplasia. Patient 4 (c.971A>G, p.Glu324Gly), a 14-year-old boy, presented on day 1 of life with tremor, hypotonia, dystonia, nystagmus, facial dysmorphism, and later seizures. MRI of the brain revealed moderate cerebellar hypoplasia.ConclusionsD-DEMØ represents an ATP1A3-related phenotype, the observation of which should trigger investigation for ATP1A3 mutations. Our findings, and the presence of multiple distinct ATP1A3-related phenotypes, support the possibility that there are differences in the underlying mechanisms.
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Project description:BACKGROUND:We undertook genetic analysis of three affected families to identify the cause of dominantly-inherited CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss) syndrome. METHODS:We used whole-exome sequencing to analyze two families affected with CAPOS syndrome, including the original family reported in 1996, and Sanger sequencing to assess familial segregation of rare variants identified in the probands and in a third, apparently unrelated family with CAPOS syndrome. RESULTS:We found an identical heterozygous missense mutation, c.2452G?>?A (p.(Glu818Lys)), in the Na?/K? ATPase ??(ATP1A3) gene in the proband and his affected sister and mother, but not in either unaffected maternal grandparent, in the first family. The same mutation was also identified in the proband and three other affected members of the second family and in all three affected members of the third family. This mutation was not found in more than 3600 chromosomes from unaffected individuals. CONCLUSION:Other mutations in ATP1A3 have previously been demonstrated to cause rapid-onset dystonia-parkinsonism (also called dystonia-12) or alternating hemiplegia of childhood. This study shows that an allelic mutation in ATP1A3 produces CAPOS syndrome.
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Project description:Variants in ATP1A3 cause neuropsychiatric disorders, especially those characterized by movement disorders. In this study, we performed whole exome sequencing for two patients with movement disorders and identified two novel heterozygous ATP1A3 variants, a missense c.2408G>A variant and an indel c.2672_2688+10delinsCAG variant. The unique indel variant occurred at the exon-intron boundary at the 3' end of exon 19, and mRNA analysis revealed that this variant caused in-frame indel alteration at the Ser891_Trp896 residue.
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Project description:Autism Spectrum Disorder (ASD) is extremely heterogeneous clinically and genetically. There is a pressing need for a better understanding of the heterogeneity of ASD based on scientifically rigorous approaches centered on systematic evaluation of the clinical and research utility of both phenotype and genotype markers. This paper presents a holistic PheWAS-inspired method to identify meaningful associations between ASD phenotypes and genotypes. We generate two types of phenotype-phenotype (p-p) graphs: a direct graph that utilizes only phenotype data, and an indirect graph that incorporates genotype as well as phenotype data. We introduce a novel methodology for fusing the direct and indirect p-p networks in which the genotype data is incorporated into the phenotype data in varying degrees. The hypothesis is that the heterogeneity of ASD can be distinguished by clustering the p-p graph. The obtained graphs are clustered using network-oriented clustering techniques, and results are evaluated. The most promising clusterings are subsequently analyzed for biological and domain-based relevance. Clusters obtained delineated different aspects of ASD, including differentiating ASD-specific symptoms, cognitive, adaptive, language and communication functions, and behavioral problems. Some of the important genes associated with the clusters have previous known associations to ASD. We found that clusters based on integrated genetic and phenotype data were more effective at identifying relevant genes than clusters constructed from phenotype information alone. These genes included five with suggestive evidence of ASD association and one known to be a strong candidate.
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Project description:We describe a child with onset of command auditory hallucinations and behavioral regression at 6 yr of age in the context of longer standing selective mutism, aggression, and mild motor delays. His genetic evaluation included chromosomal microarray analysis and whole-exome sequencing. Sequencing revealed a previously unreported heterozygous de novo mutation c.385G>A in ATP1A3, predicted to result in a p.V129M amino acid change. This gene codes for a neuron-specific isoform of the catalytic α-subunit of the ATP-dependent transmembrane sodium-potassium pump. Heterozygous mutations in this gene have been reported as causing both sporadic and inherited forms of alternating hemiplegia of childhood and rapid-onset dystonia parkinsonism. We discuss the literature on phenotypes associated with known variants in ATP1A3, examine past functional studies of the role of ATP1A3 in neuronal function, and describe a novel clinical presentation associated with mutation of this gene.
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Project description:Genetic research has shown that mutations that modify the protein-coding sequence of ATP1A3, the gene encoding the α3 subunit of Na(+)/K(+)-ATPase, cause both rapid-onset dystonia parkinsonism and alternating hemiplegia of childhood. These discoveries link two clinically distinct neurological diseases to the same gene, however, ATP1A3 mutations are, with one exception, disease-specific. Although the exact mechanism of how these mutations lead to disease is still unknown, much knowledge has been gained about functional consequences of ATP1A3 mutations using a range of in-vitro and animal model systems, and the role of Na(+)/K(+)-ATPases in the brain. Researchers and clinicians are attempting to further characterise neurological manifestations associated with mutations in ATP1A3, and to build on the existing molecular knowledge to understand how specific mutations can lead to different diseases.
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Project description:BackgroundRapid-onset dystonia parkinsonism (RDP) is a rare disease caused by ATP1A3 mutation with considerable clinical heterogeneity. Increased knowledge of RDP could be beneficial in its early diagnosis and treatment.ObjectiveThis study aimed to summarize the gene mutation spectrum of ATP1A3 associated with RDP, and to explore the correlation of ATP1A3 variants with RDP clinical phenotypes.MethodsIn this study, we reported two RDP patients from a family with a novel inherited ATP1A3 variant. Then, we reviewed and analyzed the available literature in English focused on ATP1A3-causative RDP. A total of 35 articles covering 15 families (59 patients) and 36 sporadic RDP cases were included in our analysis.ResultsThe variant A813V (2438C>T) in ATP1A3 found in our cases was a novel mutant. Delays in diagnosis were common, with a mean delay time of 14 years. ATP1A3 had distinct RDP-related mutation hotspots, which consisted of exon8, 14, 17, and 18, and the most frequently occurring variants were T613M and I578S. Approximately 74.5% of patients have specific triggers before disease onset, and 82.1% of RDPs have stable symptoms within 1 month. The incidence rates of dystonia and bradykinesia are 100 and 88.1%, respectively. The onset site varied and exhibited a rostrocaudal gradient distribution pattern in 45% of patients with RDP. Approximately 63.6% of patients had mild improvement after receiving comprehensive interventions, especially in gait disturbance amelioration.ConclusionIn patients with acute and unexplained dystonia or bradykinesia, gene screening on ATP1A3 should be timely performed. When a diagnosis has been made, treatments that may be effective are to be attempted. Our study would be helpful for the early diagnosis and treatment of ATP1T3-related RDP.
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Project description:A 21-year old male presented with ataxia and dysarthria that had appeared over a period of months. Exome sequencing identified a de novo missense variant in ATP1A3, the gene encoding the α3 subunit of Na,K-ATPase. Several lines of evidence suggest that the variant is causative. ATP1A3 mutations can cause rapid-onset dystonia-parkinsonism (RDP) with a similar age and speed of onset, as well as severe diseases of infancy. The patient's ATP1A3 p.Gly316Ser mutation was validated in the laboratory by the impaired ability of the expressed protein to support the growth of cultured cells. In a crystal structure of Na,K-ATPase, the mutated amino acid was directly apposed to a different amino acid mutated in RDP. Clinical evaluation showed that the patient had many characteristics of RDP, however he had minimal fixed dystonia, a defining symptom of RDP. Successive magnetic resonance imaging (MRI) revealed progressive cerebellar atrophy, explaining the ataxia. The absence of dystonia in the presence of other RDP symptoms corroborates other evidence that the cerebellum contributes importantly to dystonia pathophysiology. We discuss the possibility that a second de novo variant, in ubiquilin 4 (UBQLN4), a ubiquitin pathway component, contributed to the cerebellar neurodegenerative phenotype and differentiated the disease from other manifestations of ATP1A3 mutations. We also show that a homozygous variant in GPRIN1 (G protein-regulated inducer of neurite outgrowth 1) deletes a motif with multiple copies and is unlikely to be causative.
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