New ATP8A2 gene mutations associated with a novel syndrome: encephalopathy, intellectual disability, severe hypotonia, chorea and optic atrophy

Martín‐Hernández, Elena; Rodríguez‐García, María Elena; Camacho, Ana; Matilla‐Dueñas, Antoni; García‐Silva, María Teresa; Quijada‐Fraile, Pilar; Corral‐Juan, Marc; Tejada-Palacios, P.; Heras, Rogelio Simón de las; Arenas, Joaquı́n; Martín, Miguel; Martı́nez-Azorı́n, Francisco

doi:10.1007/s10048-016-0496-y

Cited by 39 publications

(47 citation statements)

References 14 publications

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“…Although these two categories of mutations display significant differences in levels of protein expression, they both can be considered as loss‐in‐function mutations since neither category displayed phospholipid activated ATPase activity. This is in agreement with clinical studies in which patients with these different missense mutations all show similar severe neurological phenotypes as found in patients homozygous for premature stop codons and frameshift mutations in the ATP8A2 gene (Alsahli et al, ; Martín‐Hernández et al, ; McMillan et al, ; Onat et al, ).…”

Section: Discussionsupporting

confidence: 89%

“…To date, seven missense mutations in ATP8A2 have been reported to cause severe neurological disorders in humans (Alsahli et al, ; Martín‐Hernández et al, ; McMillan et al, ). These include p.K429M, p.K429N, and p.W702R mutations in the phosphorylation domain (P domain), p.A544P and p.R625W mutations in the nucleotide‐binding domain (N domain), and the p.I376M and p.N917D mutations in the membrane domain of ATP8A2 (Figure a).…”

Section: Resultsmentioning

confidence: 99%

“…Genetic analysis of four members of a consanguineous Turkish family led to the discovery that a p.Ile376Met (p.I376M) mutation in ATP8A2 caused cerebellar ataxia, mental retardation, and disequilibrium (CAMRQ) syndrome (Onat et al, ). More recently, missense, nonsense, and splice‐site mutations have been found in individuals with intellectual disability, severe hypotonia, chorea, hyperkinetic movement disorders, and optic atrophy with or without cerebellar atrophy (Alsahli, Alrifai, Al Tala, Mutairi, & Alfadhel, ; Cacciagli et al, ; Martín‐Hernández et al, ; McMillan et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Expression and functional characterization of missense mutations in ATP8A2 linked to severe neurological disorders

2019

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ATP8A2 is a P4-ATPase (adenosine triphosphate) that actively flips phosphatidylserine and phosphatidylethanolamine from the exoplasmic to the cytoplasmic leaflet of cell membranes to generate and maintain phospholipid asymmetry. Mutations in the ATP8A2 gene have been reported to cause severe autosomal recessive neurological diseases in humans characterized by intellectual disability, hypotonia, chorea, and hyperkinetic movement disorders with or without optic and cerebellar atrophy. To determine the effect of disease-associated missense mutations on ATP8A2, we expressed six variants with the accessory subunit CDC50A in HEK293T cells. The level of expression, cellular localization, and functional activity were analyzed by western blot analysis, immunofluorescence microscopy, and ATPase activity assays.

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Section: Discussionsupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Expression and functional characterization of missense mutations in ATP8A2 linked to severe neurological disorders

2019

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“…Mutations in ATP8A2 have been associated with severe neurological disorders in humans (19)(20)(21)(22). The isoleucine Ile-364, which is located in the M4 transmembrane segment, is highly conserved among P4-ATPases, and the I364M mutation (I376M in human) was identified as the cause of cerebellar ataxia, mental retardation, and disequilibrium syndrome (20).…”

Section: Resultsmentioning

confidence: 99%

Phosphatidylserine flipping by the P4-ATPase ATP8A2 is electrogenic

Tadini‐Buoninsegni

Mikkelsen

Mogensen

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Phospholipid flippases (P4-ATPases) utilize ATP to translocate specific phospholipids from the exoplasmic leaflet to the cytoplasmic leaflet of biological membranes, thus generating and maintaining transmembrane lipid asymmetry essential for a variety of cellular processes. P4-ATPases belong to the P-type ATPase protein family, which also encompasses the ion transporting P2-ATPases: Ca2+-ATPase, Na+,K+-ATPase, and H+,K+-ATPase. In comparison with the P2-ATPases, understanding of P4-ATPases is still very limited. The electrogenicity of P4-ATPases has not been explored, and it is not known whether lipid transfer between membrane bilayer leaflets can lead to displacement of charge across the membrane. A related question is whether P4-ATPases countertransport ions or other substrates in the opposite direction, similar to the P2-ATPases. Using an electrophysiological method based on solid supported membranes, we observed the generation of a transient electrical current by the mammalian P4-ATPase ATP8A2 in the presence of ATP and the negatively charged lipid substrate phosphatidylserine, whereas only a diminutive current was generated with the lipid substrate phosphatidylethanolamine, which carries no or little charge under the conditions of the measurement. The current transient seen with phosphatidylserine was abolished by the mutation E198Q, which blocks dephosphorylation. Likewise, mutation I364M, which causes the neurological disorder cerebellar ataxia, mental retardation, and disequilibrium (CAMRQ) syndrome, strongly interfered with the electrogenic lipid translocation. It is concluded that the electrogenicity is associated with a step in the ATPase reaction cycle directly involved in translocation of the lipid. These measurements also showed that no charged substrate is being countertransported, thereby distinguishing the P4-ATPase from P2-ATPases.

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“…Synonymous variants were not considered. Following their respective analysis pipelines, 15 , 16 , 17 , 18 participating centers generated a list of candidate variants filtered against variants from public databases according to modes of inheritance, then compared their results through international research networks and variant databases. 19 , 20 …”

Section: Main Textmentioning

confidence: 99%

Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment

Llano-Rivas

Spaeth

Striano

et al. 2019

The American Journal of Human Genetics

110

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VAMP2 encodes the vesicular SNARE protein VAMP2 (also called synaptobrevin-2). Together with its partners syntaxin-1A and synaptosomal-associated protein 25 (SNAP25), VAMP2 mediates fusion of synaptic vesicles to release neurotransmitters. VAMP2 is essential for vesicular exocytosis and activity-dependent neurotransmitter release. Here, we report five heterozygous de novo mutations in VAMP2 in unrelated individuals presenting with a neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features. In total, we identified two single-amino-acid deletions and three non-synonymous variants affecting conserved residues within the C terminus of the VAMP2 SNARE motif. Affected individuals carrying de novo non-synonymous variants involving the C-terminal region presented a more severe phenotype with additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities. Reconstituted fusion involving a lipid-mixing assay indicated impairment in vesicle fusion as one of the possible associated disease mechanisms. The genetic synaptopathy caused by VAMP2 de novo mutations highlights the key roles of this gene in human brain development and function.

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New ATP8A2 gene mutations associated with a novel syndrome: encephalopathy, intellectual disability, severe hypotonia, chorea and optic atrophy

Cited by 39 publications

References 14 publications

Expression and functional characterization of missense mutations in ATP8A2 linked to severe neurological disorders

Expression and functional characterization of missense mutations in ATP8A2 linked to severe neurological disorders

Phosphatidylserine flipping by the P4-ATPase ATP8A2 is electrogenic

Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment

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