ATP1A3 Mutations Research Articles

Association of the canine ATP7A and ATP7B with hepatic copper accumulation in Dobermann dogs.

BackgroundHepatic copper accumulation causes chronic hepatitis in dogs. Mutations in the copper transporters ATP7A and ATP7B were, respectively, associated with attenuation and enhancement of hepatic copper concentrations in Labrador Retrievers. There is a predisposition of Dobermanns to hepatitis with increased hepatic copper concentrations.ObjectivesTo investigate whether the ATP7A:c.980C>T and ATP7B:c.4358G>A mutations identified in Labrador Retrievers were associated with hepatic copper concentrations in Dobermanns.AnimalsDobermanns from the Netherlands (n = 122) and the United States (n = 78).MethodsIn this retrospective study, mutations in ATP7A and ATP7B were investigated as risk factors for hepatic copper accumulation in Dobermanns. Liver biopsies of 200 Dobermanns were evaluated by histochemical copper staining, quantitative copper measurement, or both modalities. ATP7A and ATP7B genotypes were obtained by Kompetitive Allele Specific PCR. A linear regression model was used to investigate an association between genotype and hepatic copper concentrations.ResultsThe ATP7A:c.980C>T was identified in both Dutch (2 heterozygous individuals) and American Dobermanns. In the American cohort, the minor allele frequency of the mutation was low (.081) and a possible effect on hepatic copper concentrations could not be established from this data set. A significant association of the ATP7B:c.4358G>A variant with increased hepatic copper concentrations in Dobermanns was observed.Conclusions and Clinical ImportanceThe ATP7B:c.4358G>A variant could be a contributor to hepatic copper accumulation underlying the risk of development of copper‐associated hepatitis in breeds other than the Labrador Retriever.

Predicting copper toxicosis: relationship between the ATP7A and ATP7B gene mutations and hepatic copper quantification in dogs.

This preliminary study summarizes the genotypes of 42 Labrador Retrievers and Labrador Retriever-Golden Retriever crosses and phenotypes a subset of ten of these dogs that are homozygous mutant, heterozygous, or homozygous normal for mutations in the ATP7A and ATP7B genes that have been associated with the development of copper toxicosis in Labrador Retrievers. The purpose of this study is to evaluate whether there is a correlation between ATP7A and ATP7B genotypes and clinical evidence of hepatic pathology in young, asymptomatic Labrador Retrievers. We evaluated serum ALT levels, hepatic copper concentrations, and hepatic histopathology from ten offspring where both parents had a least one copy of the ATP7B mutation. Five were homozygous mutant, four were heterozygous, and one was homozygous normal for comparison. None had increased serum ALT activity. All dogs homozygous for the ATP7B mutation had elevated hepatic copper concentrations compared to dogs heterozygous for the ATP7B mutation regardless of sex or presence of an ATP7A mutation with the mean hepatic copper concentration being 1464ppm (reference range 100-330ppm). Mean hepatic copper concentration in homozygous normal and heterozygous dogs was 328ppm. In this preliminary analysis, we found that dogs that carry two copies of the ATP7B mutation have abnormally elevated hepatic copper levels despite having normal serum ALT activity. Our findings support the hypothesis that the ATP7B DNA test can predict defects in hepatic copper metabolism. Veterinarians can test for the ATP7B gene mutation to identify Labrador Retrievers at risk for copper toxicosis so that they can take steps to prevent development of copper-associated chronic hepatitis in their patients.

Mutations in ATP13A2 (PARK9) are associated with an amyotrophic lateral sclerosis-like phenotype, implicating this locus in further phenotypic expansion

BackgroundAmyotrophic lateral sclerosis [1] is a genetically heterogeneous neurodegenerative disorder, characterized by late-onset degeneration of motor neurons leading to progressive limb and bulbar weakness, as well as of the respiratory muscles, which is the primary cause of disease fatality. To date, over 25 genes have been implicated as causative in ALS with C9orf72, SOD1, FUS, and TARDBP accounting for the majority of genetically positive cases.ResultsWe identified two patients of Italian and French ancestry with a clinical diagnosis of juvenile-onset ALS who were mutation-negative in any of the known ALS causative genes. Starting with the index case, a consanguineous family of Italian origin, we performed whole-exome sequencing and identified candidate pathogenic mutations in 35 genes, 27 of which were homozygous. We next parsed all candidates against a cohort of 3641 ALS cases; only ATP13A2 was found to harbor recessive changes, in a patient with juvenile-onset ALS, similar to the index case. In vivo complementation of ATP13A2 using a zebrafish surrogate model that focused on the assessment of motor neuron morphology and cerebellar integrity confirmed the role of this gene in central and peripheral nervous system maintenance and corroborated the damaging direction of effect of the change detected in the index case of this study.ConclusionsWe here expand the phenotypic spectrum associated with genetic variants in ATP13A2 that previously comprised Kufor-Rakeb syndrome, spastic paraplegia 78, and neuronal ceroid lipofuscinosis type 12 (CLN12), to also include juvenile-onset ALS, as supported by both genetic and functional data. Our findings highlight the importance of establishing a complete genetic profile towards obtaining an accurate clinical diagnosis.

Neural Correlates Associated with Executive Function in Patients with ATP1A3 Mutations (S41.008)

Neural Correlates Associated with Executive Function in Patients with ATP1A3 Mutations (S41.008)

Episodic status epilepticus with hemiplegia and involuntary movements associated with novel ATP1A2 mutation (P4.6-071)

Episodic status epilepticus with hemiplegia and involuntary movements associated with novel ATP1A2 mutation (P4.6-071)

ATP7A mutations in 66 Japanese patients with Menkes disease and carrier detection: A gene analysis

Menkes disease (MNK; MIN 309400) is an X-linked recessive lethal disorder of copper metabolism caused by mutations in ATP7A (MIM 300011), which encodes a transmembrane copper-transporting P-type ATPase. This study assessed mutations in ATP7A in Japanese patients with MNK and their families using gene analysis. A total of 66 patients with MNK born between 1975 and 2013 in Japan were investigated in this study. Definite diagnosis of MNK was carried out on polymerase chain reaction (PCR) amplification and direct sequencing of each exon. Genetic analysis was also performed on 39 women for carrier diagnosis, and on nine fetuses and 10 neonates for the diagnosis of MNK. We detected 55 different mutations, of which 20 were de novo mutations. The mutations were located around the six copper binding sites, first to third and six transmembrane domains, and the ATP binding site. Of 30 mothers, 23 (76.7%) were carriers. Approximately half of the male siblings of patients with MNK were also diagnosed with MNK. Mutations in ATP7A varied widely across patients, although approximately half of the mutations were located in exons 4, 9, 10, and 15. Approximately 23% of patients did not inherit the mutations from their mothers, but had de novo mutations. An early definite diagnosis is necessary for the early treatment of MNK, and gene analysis serves as an effective method for detecting mutations in ATP7A.

Preclinical models of Wilson's disease, why dogs are catchy alternatives.

Copper toxicosis is frequently encountered in various dog breeds. A number of differences and similarities occur between Wilson disease and copper toxicosis in Bedlington terriers, caused by a mutation in the COMMD1 gene, and copper toxicosis in Labrador retrievers, caused by mutations in both ATP7A and ATP7B gene. First the specific population structure of dog breeds is explained with reference to its applicability for genetic investigations. The relatively large body size (variable from less than 1 kg to over 50 kg) and life-span (over 10 years) of dogs facilitates preclinical studies on safety on long-term effects of novel procedures. Then copper toxicosis in the two dog breeds is described in detail with an emphasis on the functions of the causative proteins. Some of the advantages of this species for preclinical studies are described with an example of liver stem cell transplantations in COMMD1 deficient dogs. Since the genetic background of copper toxicosis in other dogs' breeds has not yet been elucidated, it is conceivable that novel copper-related gene products or modifier genes will be discovered. About a century after the Novel prize was awarded to the research on dogs (Pavlov), dogs are in spotlight again as important preclinical model animals.

Na+/K+-ATPase α isoform deficiency results in distinct spreading depolarization phenotypes

Compromised Na+/K+-ATPase function is associated with the occurrence of spreading depolarization (SD). Mutations in ATP1A2, the gene encoding the α2 isoform of the Na+/K+-ATPase, were identified in patients with familial hemiplegic migraine type 2 (FHM2), a Mendelian model disease for SD. This suggests a distinct role for the α2 isoform in modulating SD susceptibility and raises questions about underlying mechanisms including the roles of other Na+/K+-ATPase α isoforms. Here, we investigated the effects of genetic ablation and pharmacological inhibition of α1, α2, and α3 on SD using heterozygous knock-out mice. We found that only α2 heterozygous mice displayed higher SD susceptibility when challenged with prolonged extracellular high potassium concentration ([K+]o), a pronounced post SD oligemia and higher SD speed in-vivo. By contrast, under physiological [K+]o, α2 heterozygous mice showed similar SD susceptibility compared to wild-type littermates. Deficiency of α3 resulted in increased resistance against electrically induced SD in-vivo, whereas α1 deficiency did not affect SD. The results support important roles of the α2 isoform in SD. Moreover, they suggest that specific experimental conditions can be necessary to reveal an inherent SD phenotype by driving a (meta-) stable system into decompensation, reminiscent of the episodic nature of SDs in various diseases.

Relapsing encephalopathy with cerebellar ataxia are caused by variants involving p.Arg756 in ATP1A3.

Mutations in ATP1A3 lead to different phenotypes having in common acute neurological decompensation episodes triggered by a specific circumstance and followed by sequelae. Alongside Alternating Hemiplegia of Childhood (AHC), Rapid-onset Dystonia Parkinsonism (RDP) and Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, Sensorineural hearing loss syndrome (CAPOS), a new Relapsing Encephalopathy with Cerebellar Ataxia (RECA) phenotype was published in 2015. We describe herein eight new pediatric cases. Most of them had no specific history when the first neurological decompensation episode occurred, before the age of 5 years, triggered by fever with severe paralytic hypotonia followed by ataxia with or without abnormal movements. Neurological sequelae with ataxia as the predominant symptom were present after the first episode in three cases and after at least one subsequent relapse in five cases. Five of the eight cases had a familial involvement with one of the two parents affected. The phenotype-genotype correlation is unequivocal with the causal substitution always located at position 756. The pathophysiology of the dysfunctions of the mutated ATPase pump, triggered by fever is unknown. Severe recurrent neurological decompensation episodes triggered by fever, without any metabolic cause, should lead to the sequencing of ATP1A3.

Fever-related ataxia: a case report of CAPOS syndrome

BackgroundCAPOS (Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy and Sensorineural hearing loss) syndrome is caused by the heterozygous mutation, c.2452G > A, in the ATP1A3 gene. Other mutations in this gene can cause a spectrum of overlapping phenotypes including alternating hemiplegia of childhood, rapid onset dystonia parkinsonism, early infantile epileptic encephalopathy and fever induced paroxysmal weakness and encephalopathy. The phenotype is still mistaken for mitochondrial/metabolic disorders and follow up studies are scare.Case presentationWe report a 20 year old Norwegian male with ataxia, sensorineural deafness and visual loss. Before the age of five he experienced three fever related episodes of acute neurological deterioration when he temporarily lost his acquired motor skills and developed persistent gait and limb ataxia. In childhood, he developed bilateral optic atrophy and bilateral sensorineural hearing loss. Motor skills improved and at age 20 the patient showed a mild ataxia, hearing loss and reduced vision. A c.2452G > A mutation in the ATP1A3 gene was identified and CAPOS syndrome was confirmed.ConclusionsThis is the first Norwegian patient reported with CAPOS syndrome. Our patient had a de novo, previously identified ATP1A3 mutation. The combination of recurrent episodes of fever related ataxia, loss of motor skills in early childhood, and early onset hearing and vision loss is typical of CAPOS syndrome. Previous reports suggest a gradual progression of the disease after the initial episodes, while this patient showed a good outcome with improvement of motor skills from adolescence long after the last deterioration episode.

Diagnostic delay in Parkinson's disease caused by PRKN mutations

ObjectiveTo confirm that there is a diagnostic delay in Parkin-related Parkinson Disease and to explore possible factors causing such a delay. MethodsWe retrospectively analyzed our patients with mutations in the parkin RBR E3 ubiquitin protein ligase gene (PRKN). We collected a total of 34 patients and focused on 18 cases (14 homozygous, 4 compound heterozygous). An arbitrary cut-off of 10 years from disease onset to diagnosis was considered to define patients with delayed diagnosis. ResultsEight of 18 cases had a significant delay in their diagnosis (25.3 ± 17 years). By comparing patients with and without a delayed diagnosis and subsequently, comparing these groups to a group of young onset PD negative for mutations of PRKN, SNCA, DJ1, PINK1, LRRK2, GBA, and ATP13A2, we identified a specific phenotype associated with a diagnostic delay: young age, lack of tremor, and involvement of lower limbs (particularly dystonia affecting gait) at the time of disease onset. ConclusionsOur findings emphasize the diverse phenotypes associated with PRKN mutations and the related diagnostic challenges they present.

Familial Hemiplegic Migraine: A New Gene in an Italian Family

Hemiplegic migraine (HM) is a rare form of migraine characterized by severe attacks of unilateral and pulsating headache (associated with photophobia, phonophobia or nausea). To date, mutations in three different genes, ATP1A2, CACNA1A and SCN1A, are known to cause familial hemiplegic migraine (FHM) or sporadic hemiplegic migraine (SHM) phenotype, while mutations in ATP1A3 were recently associated to alternating hemiplegia of childhood (AHC). Here we report an Italian family who presented with familial hemiplegic migraine, carrier of an heterozygous ATP1A4 mutations c.1798 C>T, predicted to cause the p. (Pro600Ser) amino acid substitution, which segregated with the disease phenotype in four members. The variant, identified by using whole exome sequencing combined with Sanger sequencing, was predicted to be disease-causing by prediction software and to affect protein stability by thermodynamic study. To our knowledge, this is the first report of a mutation of ATP1A4 gene, associated to FHM, thus useful to further expand our understanding of the molecular etiology of HM. Furthermore, our evidence may suggest to consider ATP1A4 in addition to ATP1A2, ATP1A3, CACNA1A and SCN1A, in genetic screening of patients affected by HM.

Alternating Hemiplegia of Childhood Caused by ATP1A3 Mutations: A Report of Two Cases

Alternating hemiplegia of childhood is a rare neurodevelopmental disorder. Most cases are reported as sporadic disorder due to de novo variants, and few with family members involved. Two boys were hospitalized due to epileptic seizures occurred initially at age of six to seven months. During the course of the disease, there were repeated episodes of paroxysmal weakness or paralysis affecting one side of the body. Genetic testing showed that both patients carried heterozygous missense mutations in the ATP1A3 gene (OMIM: 614820): c.3025 (exon 22) A>G (p.K1009E) and c.2443 (exon 18) G>A (p.E815K). Flunarizine can significantly improve the paroxysmal motor symptoms of pediatric patients with alternating hemiplegia.

'Atypical' Parkinson's disease - genetic.

Genetic atypical Parkinson's disease (PD) describes monogenic forms of PD that resemble idiopathic PD but feature prominent atypical clinical signs and symptoms and can be sub-grouped into i) atypical monogenic forms caused by mutations in the ATP13A2, DNAJC6, FBXO7, SYNJ1, VPS13C, and DCTN genes; ii) monogenic PD more closely resembling idiopathic PD, but associated with atypical features in at least a subset of cases (SNCA-, LRRK2-, VPS35-, Parkin-, PINK1-, and DJ-1-linked PD; iii) carriers of mutations in genes that are usually associated with other movement disorders but may present with parkinsonism, such as dopa-responsive dystonia. Some atypical features are shared by almost all forms, such as an overall early age at onset. Other clinical signs are present in carriers of mutations across several different genes, such as for example, early cognitive decline. Finally, several clinical features can serve as red flags for specific forms of atypical PD including a supranuclear gaze palsy in ATP13A2 mutation carriers or hypoventilation linked to mutations in the DCTN1 gene.

ATP13A2 facilitates HDAC6 recruitment to lysosome to promote autophagosome–lysosome fusion

Mutations in ATP13A2 cause Kufor-Rakeb syndrome, an autosomal recessive form of juvenile-onset atypical Parkinson's disease (PD). Recent work tied ATP13A2 to autophagy and other cellular features of neurodegeneration, but how ATP13A2 governs numerous cellular functions in PD pathogenesis is not understood. In this study, the ATP13A2-deficient mouse developed into aging-dependent phenotypes resembling those of autophagy impairment. ATP13A2 deficiency impaired autophagosome-lysosome fusion in cultured cells and in in vitro reconstitution assays. In ATP13A2-deficient cells or Drosophila melanogaster or mouse tissues, lysosomal localization and activity of HDAC6 were reduced, with increased acetylation of tubulin and cortactin. Wild-type HDAC6, but not a deacetylase-inactive mutant, restored autophagosome-lysosome fusion, antagonized cortactin hyperacetylation, and promoted lysosomal localization of cortactin in ATP13A2-deficient cells. Mechanistically, ATP13A2 facilitated recruitment of HDAC6 and cortactin to lysosomes. Cortactin overexpression in cultured cells reversed ATP13A2 deficiency-associated impairment of autophagosome-lysosome fusion. PD-causing ATP13A2 mutants failed to rescue autophagosome-lysosome fusion or to promote degradation of protein aggregates and damaged mitochondria. These results suggest that ATP13A2 recruits HDAC6 to lysosomes to deacetylate cortactin and promotes autophagosome-lysosome fusion and autophagy. This study identifies ATP13A2 as an essential molecular component for normal autophagy flux in vivo and implies potential treatments targeting HDAC6-mediated autophagy for PD.

Genotype-phenotype correlations in Darier disease: A focus on the neuropsychiatric phenotype.

Darier disease (DD) is an autosomal dominant skin disorder caused by mutations in ATP2A2 encoding the sarco/endoplasmic reticulum Ca2+ ATPase Isoform 2 (SERCA2). Evidence of a population-level association between DD and psychiatric disorders suggests that mutations in ATP2A2 may have pleiotropic effects on the brain as well as skin. Evidence of genotype-phenotype relationships between ATP2A2 mutations and neuropsychiatric phenotypes would further support this suggestion. We investigated genotype-phenotype correlations between lifetime neuropsychiatric features and ATP2A2 mutation type (dichotomized into likely gene disrupting [LGD] or protein altering) in 75 unrelated individuals with DD. We also looked for evidence of clustering of mutations within SERCA2 according to neuropsychiatric features. Combining our data with the existing literature, the rate of LGD mutations was found to be significantly higher among DD cases/families with bipolar disorder, schizophrenia, or affective psychosis (p = .011). We also found a significant relationship between mutations located in the S4-M4 region of the protein and the presence of a severe neuropsychiatric phenotype (p = .032). Our findings add support to the hypothesis that Darier-causing mutations in ATP2A2 confer susceptibility to neuropsychiatric dysfunction, in particular severe psychiatric illness. This, together with evidence from research on common polymorphisms confirms ATP2A2 as a gene at which variation influences susceptibility to major psychiatric illness.

Hereditary ataxias and paraparesias: clinical and genetic update.

This review aims at updating the clinical and genetic aspects of hereditary spastic paraplegias (HSPs) and hereditary cerebellar ataxias (HCAs), focusing on the concept of spastic-ataxia phenotypic spectrum and on newly identified clinical overlaps with other neurological and nonneurological diseases. Next-generation sequencing (NGS) has allowed the discovery of new genes involved in HSPs and HCAs. They include new HCAs genes such as GRM1 (SCA44), FAT2 (SCA45), PLD3 (SCA46), SCYL1 (SCAR21), UBA5 (SCAR24) and XRCC1 (SCAR26) as well as CAPN1 (SPG76) and CPT1C (SPG73) in HSPs. Furthermore, NGS allowed enriching known genes phenotype, reinforcing the overlap between HSPs and HCAs defining the spastic ataxia spectrum. Clear examples are the expanded phenotypes associated with mutations in SPG7, PNPLA6, GBA2, KIF1C, CYP7B1, FA2H, ATP13A2 and many others. Moreover, other genes not previously linked to HCAs and HSPs have been implicated in spastic or ataxic phenotypes. The increase of HSPs and HCAs-related phenotypes and the continuous discovery of genes complicate clinical diagnostic in practice but, at the same time, it helps highlighting common pathological pathways, therefore opening new ways to the development of common therapeutic approaches.

Cerebellar Ataxia with Progressive Optic Atrophy and Deafness (CAPOS Syndrome): A Rare Case Report

CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss) is a rare autosomal dominant disorder caused by ATP1A3 mutation. Fever triggered cerebellar dysfunction along with progressive optic atrophy and sensorineural deafness are typical features. Herein, we report a 20-year-old female with multiple fever induced cerebellar dysfunction with partial improvement. Pendular nystagmus and optic atrophy were prominent which were also present in patient’s younger sister. As there was progressive sensorineural hearing loss and areflexia, CAPOS syndrome was diagnosed. Though specific therapy is yet to be developed, acetazolamide, cochlear implantation, visual aid and family screening may improve quality of life. Bangladesh Journal of Neuroscience 2018; Vol. 34 (2): 110-114

Menkes disease: Oral administration of glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) rescues the macular mouse.

Menkes disease is a copper metabolism disorder caused by mutations in ATP7A, a copper-transporting P-type ATPase. In this study, oral copper supplementation via glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) (CuGTSM), a lipophilic copper complex, was investigated in male hemizygous macular (MoMl/y) mice, a mouse model of Menkes disease. CuGTSM was administered by oral gavage on postnatal days 5, 8, 11, 17, 23, and 32. The copper levels in the organs and serum, copper-dependent enzyme activities in the brain, and ceruloplasmin (Cp) activity in the serum were measured at 15 days and 3 and 8 months of age. Histological analysis of the intestines and the rotarod test were also performed. CuGTSM treatment extended the lifespan of MoMl/y mice and partly restored the copper concentrations and cytochrome oxidase and DBH activities in the brain; however, the rotarod test showed impaired motor performance. The treatment also increased copper concentrations and Cp activity in the serum. In suckling MoMl/y mice, CuGTSM treatment transiently induced diarrhea accompanied by copper accumulation and altered villus morphology in the ileum. Oral administration of CuGTSM extended the lifespan of MoMl/y mice. Oral administration is attractive, but pharmaceutical studies are needed to reduce the adverse enteral effects.

Partial loss of ATP13A2 causes selective gliosis independent of robust lipofuscinosis

Loss-of-function mutations in ATP13A2 are associated with three neurodegenerative diseases: a rare form of Parkinson's disease termed Kufor-Rakeb syndrome (KRS), a lysosomal storage disorder termed neuronal ceroid lipofuscinosis (NCL), and a form of hereditary spastic paraplegia (HSP). Furthermore, recent data suggests that heterozygous carriers of mutations in ATP13A2 may confer risk for the development of Parkinson's disease, similar to the association of mutations in glucocerebrosidase (GBA) with both Parkinson's disease and Gaucher's disease, a lysosomal storage disorder. Mutations in ATP13A2 are generally thought to be loss of function; however, the lack of human autopsy tissue has prevented the field from determining the pathological consequences of losing functional ATP13A2. We and others have previously neuropathologically characterized mice completely lacking murine Atp13a2, demonstrating the presence of lipofuscinosis within the brain – a key feature of NCL, one of the diseases to which ATP13A2 mutations have been linked. To determine if loss of one functional Atp13a2 allele can serve as a risk factor for disease, we have now assessed heterozygous Atp13a2 knockout mice for key features of NCL. In this report, we demonstrate that loss of one functional Atp13a2 allele leads to both microgliosis and astrocytosis in multiple brain regions compared to age-matched controls; however, levels of lipofuscin were only modestly elevated in the cortex of heterozygous Atp13a2 knockout mice over controls. This data suggests the possibility that partial loss of ATP13A2 causes inflammatory changes within the brain which appear to be independent of robust lipofuscinosis. This study suggests that heterozygous loss-of-function mutations in ATP13A2 are likely harmful and indicates that glial involvement in the disease process may be an early event that positions the CNS for subsequent disease development.