ATP7A Research Articles

Lasting Electrographic Footprint of Familial Hemiplegic Migraine (P7-12.005)

<h3>Objective:</h3> We describe a case of familial hemiplegic migraine whose EEG showed uni-hemispheric slowing during the episode and weeks following it. <h3>Background:</h3> Electroencephalograms (EEGs) are not routinely done in the context of a migraine diagnosis. EEG abnormalities have been reported in pediatric migraines including slow activity that is diffuse, lateralized or focal. Specific to hemiplegic migraine, slowing has been described in the hemisphere contralateral to the hemiplegic limb. <h3>Design/Methods:</h3> NA <h3>Results:</h3> A twelve-year-old, previously healthy, right-handed girl presented to the emergency department with sudden onset right arm weakness, aphasia and confusion. Altered mentation, expressive aphasia and right hemiparesis were noted. She underwent emergent MRI brain for concerns of acute stroke, which ruled out the same. Continuous EEG monitoring showed marked left hemispheric slowing but no focal seizures. For suspicion of complex hemiplegic migraine, she received a combination of ketorolac, diphenhydramine and prochlorperazine. This led to resolution of weakness and aphasia, along with return to baseline mentation. However, left hemispheric slowing persisted on EEG even at the time of discharge. Two weeks later, a repeat routine EEG showed continued slowing in the left occipital region, while patient clinically continued to function at baseline and had not had any further episodes. Four weeks after the original event, EEG returned to symmetric brain activity with no other abnormalities. Subsequently, family shared that patient’s mother and maternal aunt experience symptoms consistent with hem legic migraines, but had never been formally diagnosed. With this crucial information, we proceeded with genetic testing which revealed a mutation in the ATP1A2 gene, establishing the diagnosis as Familial Hemiplegic Migraine (FHM). <h3>Conclusions:</h3> With limited literature on EEG abnormalities seen in pediatric migraines, specifically familial hemiplegic migraines, our case is the first report of EEG changes persisting for weeks beyond the resolution of symptoms from an acute episode. <b>Disclosure:</b> Dr. Ahmed Khan has nothing to disclose. Cynthia Morris has nothing to disclose. Dr. Goretzke has nothing to disclose.

A novel CACNA1A variant causing Developmental and Epileptic Encephalopathy 42: Report of the first case in Colombia (P3-1.010)

<h3>Objective:</h3> To report a CACNA1A Novel variant causing Developmental and Epileptic Encephalopathy 42. <h3>Background:</h3> CACNA1A encodes the α1A subunit (pore-forming subunit) of a neuronal P/Q type calcium channel. Mutations within this gene lead to clinically significant neurological abnormalities with multiple phenotypic presentations, including Familial Hemiplegic Migraine (FHM), episodic ataxia type 2 (EA2), spinocerebellar ataxia type 6 (SCA6), and Developmental and Epileptic Encephalopathy 42 (DEE42). DEE42 is a disorder characterized by the developmental delay with cognitive impairment and multiple types of seizures in the neonatal period. <h3>Design/Methods:</h3> A karyotype was performed using peripheral blood lymphocytes. A Microarray-based Comparative Genomic Hybridization (aCGH) using CytoScan 750K Array (Affymetrix, Santa Clara, CA, USA) and whole exome sequencing (WES). <h3>Results:</h3> Our patient is a female born to non-consanguineous parents with a family history of speech and psychomotor developmental delay in her mother. She was born at term with uneventful antenatal and perinatal history. At 12 months, she presented to the Neurology and Genetics department with macrocephaly, frontal bossing, severe hypotonia, psychomotor delay, and repeated episodes of seizures requiring therapy with valproic acid and levetiracetam. EEG evidenced generalized spike waves. Her course was complicated by a traumatic brain injury that precipitated repeated episodes of status epilepticus. At 28 months old, she had cognitive and communication deficits with severe speech delay. The aCGH showed a 4q21.21 deletion. The final result was given as 46, XX arr[GRCh37/hg19] chr4:79766081-80327420. In this study, we describe a patient with DEE42 due to a novel mutation in CACNA1A identified using WES. WES revealed a novel heterozygous variant in the CACNA1A gene: c.4174G&gt;A (p.Val1392Met). Parent analysis was negative for the mutation. This novel variant was predicted as a disease-causing mutation. <h3>Conclusions:</h3> These findings widen the mutation and phenotypic spectrum of CACNA1A-associated disease. The potential genotype-phenotype correlation would facilitate early identification and help guide future pharmacologic treatment research. <b>Disclosure:</b> Dr. Orellana Zambrano has nothing to disclose. Dr. Candelo has nothing to disclose. Mrs. Diaz has nothing to disclose. Dr. Pacheco has nothing to disclose. Mr. Giraldo-Ocampo has nothing to disclose. Dr. Gomez-Pineda has nothing to disclose. Dr. Pachajoa has nothing to disclose.

Brody myopathy associated with novel compound heterozygous ATP2A1 mutations (P6-8.015)

<h3>Objective:</h3> To describe a case of presumed Brody myopathy associated with novel compound heterozygous ATP2A1 mutations. <h3>Background:</h3> Brody myopathy is a rare autosomal recessive skeletal muscle disease characterized by exertional muscle cramps, weakness, and/or rhabdomyolysis associated with clinical myotonia. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> A 19-year-old man with normal development and motor milestones presented to neuromuscular clinic after two episodes of exercise-induced muscle weakness and rhabdomyolysis in the past 6-months. Peak creatinine phosphokinase (CPK) was &gt;63,000 units/L and he quickly returned to baseline after each episode with intravenous fluids and supportive care. Remaining initial testing including serum total carnitine and acylcarnitine levels, and urine organic acid levels, were normal. He provided additional history of progressive difficulty relaxing leg and handgrip muscles after exertion since childhood, and multiple episodes of asymptomatic dark-colored urine provoked by strenuous exercise over the past two years. Physical examination showed bilateral grip and percussion myotonia with otherwise normal muscle bulk, strength, and remaining neurologic examination. Electromyography was normal. Genetic testing including myotonic dystrophy types 1 and 2, Pompe disease, and non-dystrophic myotonic disorders was notable for compound heterozygous ATP2A1 gene c.2032C&gt;T (p.Arg678Cys) and c.2176G&gt;A (p.Val726Met) variants of uncertain significance. Separate pathogenic mutations in this gene cause Brody myopathy, a non-dystrophic myotonic disorder characterized by exertional rhabdomyolysis. The patient is presumed to have Brody myopathy due to novel compound heterozygous ATP2A1 mutations. <h3>Conclusions:</h3> Brody myopathy should be considered in individuals presenting with muscle cramps, clinical myotonia, and exertional rhabdomyolysis. Clinical features and electromyographic findings are milder than myotonic dystrophies, Pompe disease, and typical non-dystrophic myotonic disorders. Genetic testing including ATP2A1 gene sequencing aids diagnosis. Management is supportive, although individuals should be aware of a 5% association with malignant hyperthermia-like episodes after exposure to volatile anesthetics. <b>Disclosure:</b> Dr. Walia has nothing to disclose. Dr. Su has nothing to disclose.

Clinical features and genetic analysis of two Chinese ATP1A2 gene variants pedigrees of familial hemiplegic migraine

ObjectiveTo analyze the clinical manifestations and genetic examination results of affected members of two Chinese ATP1A2 gene variants pedigrees, and to summarize their phenotypic and genotypic features. MethodsThe clinical features were recorded in detailed. The cranial magnetic resonance imaging for patients and gene sequencing of two Chinese ATP1A2 gene variant pedigrees were perform. The correlation between the types of variants and the clinical phenotypes of ATP1A2 gene were analyzed. ResultsThese two pedigrees are diagnosed as familial hemiplegic migraine type 2 (FHM2) with ATP1A2 heterozygous missense variants, c.1091C > T (p.T364M) found in pedigree 1 and c.899T > C (p.L300P) in pedigree 2. Multiple phenotypes coexist in both families, and the two probands have severe cranial magnetic resonance imaging manifesting hemiplegic contralateral cortical swelling and diffusion weighted imaging hyperintense signal, which can be fully recovered. ATP1A2 gene variants were seen in FHM2, sporadic hemiplegic migraine and atypical alternating hemiplegia of childhood (AHC) families or sporadic cases, etc. The clinical features of ATP1A2 variant c.1091C > T (p.T364M) are basically similar in Chinese patients and European patients. ConclusionThese two Chinese pedigrees had FHM2 due to ATP1A2 heterozygous missense variation. It would expand the understanding of ATP1A2.

Evaluating Dysfunction in Fever-Induced Paroxysmal Weakness and Encephalopathy

Heterozygous variants in the ATP1A3 gene are linked to well-known neurological phenotypes. There has been growing evidence for a separate phenotype associated with variants in residue Arg756-fever-induced paroxysmal weakness and encephalopathy (FIPWE) or relapsing encephalopathy with cerebellar ataxia (RECA). With only about 20 cases being reported, the clinical features associated with mutations at Arg756 have not been fully elucidated. We report a case of FIPWE with a p.Arg756Cys change in the ATP1A3 gene and a comparison of the clinical features, including electrophysiological examination, with previous cases. The 3-year-old male patient had normal psychomotor development, presenting with recurrent symptoms of generalized hypotonia with loss of gait, mutism, and dystonic movements only during febrile illnesses since 19 months of age. At 2.7 years of age, a third neurological decompensation episode occurred, during which electroencephalography (EEG) did not reveal high voltage slow waves or epileptiform discharge. Nerve conduction studies (NCS) also did not show latency delay or amplitude reduction. ATP1A3 exon sequencing showed a heterozygous p.Arg756Cys mutation. While the patient experienced repeated encephalopathy-like episodes, including severe hypotonia during febrile illness, EEG and NCS did not reveal any obvious abnormalities. These electrophysiological findings may represent an opportunity to suspect FIPWE and RECA.

Hypercontractile Cardiac Phenotype in Mice with Migraine-Associated Mutation in the Na+,K+-ATPase α2-Isoform.

Two α-isoforms of the Na+,K+-ATPase (α1 and α2) are expressed in the cardiovascular system, and it is unclear which isoform is the preferential regulator of contractility. Mice heterozygous for the familial hemiplegic migraine type 2 (FHM2) associated mutation in the α2-isoform (G301R; α2+/G301R mice) have decreased expression of cardiac α2-isoform but elevated expression of the α1-isoform. We aimed to investigate the contribution of the α2-isoform function to the cardiac phenotype of α2+/G301R hearts. We hypothesized that α2+/G301R hearts exhibit greater contractility due to reduced expression of cardiac α2-isoform. Variables for contractility and relaxation of isolated hearts were assessed in the Langendorff system without and in the presence of ouabain (1 µM). Atrial pacing was performed to investigate rate-dependent changes. The α2+/G301R hearts displayed greater contractility than WT hearts during sinus rhythm, which was rate-dependent. The inotropic effect of ouabain was more augmented in α2+/G301R hearts than in WT hearts during sinus rhythm and atrial pacing. In conclusion, cardiac contractility was greater in α2+/G301R hearts than in WT hearts under resting conditions. The inotropic effect of ouabain was rate-independent and enhanced in α2+/G301R hearts, which was associated with increased systolic work.

NOTCH2, ATIC, MRI1, SLC6A13, ATP13A2 Genetic Variations are Associated with Ventricular Septal Defect in the Chinese Tibetan Population Through Whole-Exome Sequencing.

Ventricular septal defect (VSD) is the most common congenital cardiac abnormality in children and the second most common in adults. This study aimed to explore the potentially causative genes in VSD patients in the Chinese Tibetan population, and to provide a theoretical basis for the genetic mechanism of VSD. Peripheral venous blood was collected from 20 VSD subjects, and whole-genome DNA was extracted. High-throughput sequencing was performed on qualified DNA samples using whole-exome sequencing (WES) technology. After filtering, detecting, and annotating qualified data, single nucleotide variations (SNVs) and insertion-deletion (InDel) markers were analyzed, and data processing software such as GATK, SIFT, Polyphen, and MutationTaster were used for comparative evaluation and prediction of pathogenic deleterious variants associated with VSD. A total of 4793 variant loci, including 4168 SNVs, 557 InDels and 68 unknown loci and 2566 variant genes were obtained from 20 VSD subjects through bioinformatics analysis. According to the screening of the prediction software and database, the occurrence of VSD was predicted to be associated with five inherited pathogenic gene mutations, all of which were missense mutations, including NOTCH2 (c.1396C >A:p.Gln466Lys), ATIC (c.235C >T:p.Arg79Cys), MRI1 (c.629G >A:p.Arg210Gln), SLC6A13 (c.1138G >A:p.Gly380Arg), ATP13A2 (c.1363C >T:p.Arg455Trp). This study demonstrated that NOTCH2, ATIC, MRI1, SLC6A13, ATP13A2 gene variants were potentially associated with VSD in Chinese Tibetan population.

Ethics in pre-ART genetics: a missed X-linked Menkes disease case

Assisted reproductive technology (ART) has experienced dramatic progress over the last 30 years, and gamete donation is routine in fertility clinics. Major advances in genetic diagnostics are part of this development due to the ability to analyze multiple genes or whole genomes fast and to an affordable prize. This requires knowledge and capability to evaluate genetic variants correctly in a clinical setting. Here we report a Menkes disease case, born after ART, where genetic screening and variant scoring failed to identify an egg donor as carrier of this fatal X-linked disorder. The gene variant is a deletion of a single base pair leading to a frameshift and premature termination of the protein, predicted to result in no or severely diminished function. The variant would be classified as likely pathogenic (class 4) and should be readily detectable by molecular genetic screening techniques. We wish to highlight this case to prevent future similar cases. IVI Igenomix has developed and embarked on an ambitious screening program to detect and prevent a large number of inherited severe childhood disorders in ART pregnancies. The company has recently achieved ISO 15189 certification with competence to evaluate and deliver timely, accurate, and reliable results. Failure to identify a pathogenic variant in the ATP7A gene leading to birth of two boys with Menkes disease invokes the required procedures to screen and detect disease-causing gene variants. This calls for ethical and legal considerations in ART diagnostics to prevent fatal errors like the present.

Editing of HSF-1 and Na/K-ATPase α1 subunit by CRISPR/Cas9 reduces thermal tolerance of bovine skin fibroblasts to heat shock in vitro

A follow-up to our previous findings, the present study was planned to evaluate the role of Na/K-ATPase alpha1-subunit (ATP1A1) gene in heat shock tolerance. The primary fibroblast culture was established using ear pinna tissue samples of Sahiwal cattle (Bos indicus). The knockout cell lines of Na/K-ATP1A1 and HSF-1 (heat shock factor-1, as a positive control) genes were developed by CRISPR/Cas9 method and the gene-editing was confirmed by the genomic cleavage detection assay. The two knockout cell lines (ATP1A1 and HSF-1) and wild-type fibroblasts were exposed to heat shock at 42 °C in vitro and different cellular parameters viz., apoptosis, proliferation, mitochondrial membrane potential (ΔΨm ), oxidative stress, along with expression pattern of heat-responsive genes were studied. The results showed that in vitro heat shock given to knockout fibroblast cells of both ATP1A1 and HSF-1 genes resulted in decreased cell viability, while increasing the apoptosis rate, membrane depolarization, and ROS levels. However, the overall impact was more in HSF-1 knockout cells as compared to ATP1A1 knockout cells. Taken together, these results indicated that the ATP1A1 gene plays a critical role as HSF-1 under heat stress and helps cells to cope with heat shock.

Heterozygous ATP2A2 missense variant identified in a Shih Tzu with Darier disease.

Darier disease is caused by heterozygous loss of function variants in the ATP2A2 gene encoding the endoplasmic/sarcoplasmic reticulum Ca2+ pump ATP2A2. Defective intracellular calcium signaling in the epidermis results in a loss of desmosomal adhesion and the development of characteristic skin lesions. In this study, we investigated a Shih Tzu that developed erythematous papules on the ventrum and, over time, the dorsal neck and a nodule in the right ear canal with secondary ear infection. Histopathologic examination demonstrated discrete foci of acantholysis affecting suprabasal layers of the epidermis. Whole genome sequencing of the affected dog identified a heterozygous missense variant, p.N809H, affecting an evolutionarily conserved amino acid residue of the ATP2A2 protein. The highly characteristic clinical and histopathologic findings together with a plausible variant in the only known functional candidate gene establish the diagnosis of canine Darier disease in the studied dog and highlight the potential of genetic analyses as complementary diagnostic approach in veterinary medicine.

The role of ATP1A3 gene in epilepsy: We need to know more.

The ATP1A3 gene, which encodes the Na+/K+-ATPase α3 catalytic subunit, plays a crucial role in both physiological and pathological conditions in the brain, and mutations in this gene have been associated with a wide variety of neurological diseases by impacting the whole infant development stages. Cumulative clinical evidence suggests that some severe epileptic syndromes have been linked to mutations in ATP1A3, among which inactivating mutation of ATP1A3 has been intriguingly found to be a candidate pathogenesis for complex partial and generalized seizures, proposing ATP1A3 regulators as putative targets for the rational design of antiepileptic therapies. In this review, we introduced the physiological function of ATP1A3 and summarized the findings about ATP1A3 in epileptic conditions from both clinical and laboratory aspects at first. Then, some possible mechanisms of how ATP1A3 mutations result in epilepsy are provided. We think this review timely introduces the potential contribution of ATP1A3 mutations in both the genesis and progression of epilepsy. Taken that both the detailed mechanisms and therapeutic significance of ATP1A3 for epilepsy are not yet fully illustrated, we think that both in-depth mechanisms investigations and systematic intervention experiments targeting ATP1A3 are needed, and by doing so, perhaps a new light can be shed on treating ATP1A3-associated epilepsy.

Analysis of Potential Genes and Economic Parameters Associated with Growth and Heat Tolerance in Sheep (Ovis aries).

This study explored the potential genes and economic factors that might be associated with growth and heat tolerance in two sheep breeds. Data on growth performance from the third month to six months of age were obtained based on records. In comparison to Aboudeleik lambs, Barki lambs developed considerably greater starting body weight, final body weight, final body weight gain, daily weight gain, and percentage increase in BW/month. Single nucleotide polymorphisms (SNPs) were found between lambs of the two breeds using PCR-DNA sequencing of CAST, LEP, MYLK4, MEF2B, STAT5A, TRPV1, HSP90AB1, HSPB6, HSF1, ST1P1, and ATP1A1 genes. Lambs from each breed were divided into groups based on detected SNPs in genes related to growth. The least squares means of the differentiated groups revealed a significant correlation of detected SNPs with growth and heat tolerance attributes (p ≤ 0.05). Barki lambs elicited greater total variable costs, total costs, total return, and net return values. The Barki sheep provided the best economic efficiency value when comparing the percentage difference between net profit and economic efficiency. Together with economic considerations, SNPs found may be used as proxies for marker-assisted selection of the best breed of sheep for traits related to growth and heat tolerance.

Identification of a robust scoring system based on metabolic genes followed by in-depth validation of ATP1A3 in glioma

AimsIn the past few decades, the prognosis of glioma patients has not significantly improved. Therefore, to provide more precise medical services for glioma patients, it is urgent to identify more clinically meaningful subtypes, establish more robust clinical prediction models, and find more effective therapeutic targets. Materials and methodsFour distinct metabolic-associated subtypes were identified by the NMF algorithm based on metabolic genes (MEGs). A robust scoring system was constructed based on the differentially expressed genes (DEGs) screened from the four metabolic-associated subtypes with the LASSO regression algorithm and multivariate Cox regression analysis. Further analysis of scoring systems was done by different R packages. In addition, the ATP1A3 gene was screened and bioinformatics analysis of it was conducted on several public websites. GSEA software was utilized to search hallmark signaling pathways closely related to ATP1A3. Cytological experiments were used to investigate the role of ATP1A3 in the malignant progression of glioblastoma (GBM) cells. Key findingsFour metabolic-associated subtypes with significantly different clinicopathological characteristics were identified, and a robust scoring system with outstanding clinical application value was established. In addition, a tumor suppressor gene ATP1A3 was found, which is expected to be a potential therapeutic target for glioma. SignificanceThis study is of great significance in the diagnosis, prognosis, and prediction of the response to immune checkpoint blockers (ICBs) for glioma patients. More importantly, this study found a potential therapeutic target for glioma.

Heterozygous de novo mutation in the ATP1A2 gene in a patient with alternating hemiplegia of childhood

Heterozygous de novo mutation in the ATP1A2 gene in a patient with alternating hemiplegia of childhood

ATP1A3基因Arg756位点变异相关疾病

ATP1A3基因Arg756位点变异相关疾病

Copper transporter gene ATP7A: A predictive biomarker for immunotherapy and targeted therapy in hepatocellular carcinoma.

ATP7A is an important copper transporter that regulates numerous cellular biological processes. However, the role of ATP7A in immunotherapy and targeted therapy, especially for hepatocellular carcinoma (HCC), remains unknown. We analyzed ATP7A expression and its effect on digestive system tumor prognoses, assessed its expression in tissue microarrays from 319 HCC patients, and investigated the relationship between ATP7A expression and tumor immunity. Specifically, we evaluated the possible association between ATP7A and programmed death ligand 1 (PD-L1) expression in human HCC tissues. Finally, we analyzed the effect of ATP7A on sorafenib efficacy in HCC. ATP7A is generally highly expressed in digestive system tumors but related to poor prognosis only in HCC. ATP7A levels are positively associated with immune cell infiltration and immune checkpoint expression (especially PD-L1). HCC patients coexpressing APT7A and PD-L1 demonstrate poor prognoses. Moreover, HCC patients with high ATP7A levels were more sensitive to sorafenib and demonstrated higher survival rates after sorafenib treatment. This study provides insights into the correlation between ATP7A levels and tumor immune infiltration and immune checkpoint function in HCC, sheds light on the significance of ATP7A in cancer progression, and provides guidance for more effective and general therapeutic strategies.

Machine learning screening for Parkinson's disease-related cuproptosis-related typing development and validation and exploration of personalized drugs for cuproptosis genes.

Parkinson's disease (PD) is a common, degenerative disease of the nervous system that is characterized by the death of dopaminergic neurons in the substantia nigra densa (SNpc). There is growing evidence that copper (Cu) is involved in myelin formation and is involved in cell death through modulation of synaptic activity as well as neurotrophic factor-induced excitotoxicity. This study aimed to explore potential cuproptosis-related genes (CRGs) and immune infiltration patterns in PD and the development of Cu chelators relevant for PD treatment. The PD datasets GSE7621, GSE20141, and GSE49036 were downloaded from the Gene Expression Omnibus (GEO) database. The consensus clustering method was used to classify the specimens of PD. Using weighted gene co-expression network analysis (WGCNA) and random forest (RF) tree model, support vector machine (SVM) learning model, extreme gradient boosting (XGBoost) model, and general linear model (GLM) algorithms to screen disease progression-related models, the column charts were created to verify the accuracy of these CRGs in predicting PD progression. Single sample genomic enrichment analysis (ssGSEA) was used to estimate the correlation between genes associated with copper poisoning and genes associated with immune cells and immune function. Molecular docking was used to verify interactions with copper chelating agents associated with cuproptosis for PD treatment. Through ssGSEA, we identified three copper poisoning related genes ATP7A, NFE2L2 and MTF1, which are related to immune cells in PD. We also verified that LAGASCATRIOL can bind to NFE2L2 through molecular docking. Consistent cluster analysis identified two subtypes, among which C2 subtype was just enriched in PD. And to more accurately diagnose PD progression, patients can benefit from a feature map based on these genes. CRGs such as NFE2L2, MTF1, and ATP7B were identified to be associated with the pathogenesis of PD and provide a possible new direction for the treatment of PD, which needs further in-depth study.

Determination of ATP1A1 Gene Polymorphism in the Turkish Holstein Cattle

Heat stress is an important factor negatively affecting the productive characteristics, immune response and reproductive performance of livestock. Sustainable livestock systems that can tolerate the impact of increasing environmental temperature are very important to ensure global food security. Oxidative stress triggered by heat stress influences plasma Na and K levels in cattle. The ATP1A1 gene encodes the α1 isoform that forms the transmembrane subunit of the NA,K ATPase enzyme. The α subunit plays a major role in maintaining sodium-potassium homeostasis in all animal cells. The aim of the study was to determine ATP1A1 gene polymorphisms in Turkish Holstein cattle. The target regions (intron 17 and exon 18) were amplified and sequenced in 50 Turkish Holstein cattle. Multiple alignments revealed three SNP. rs109703332 A>G and rs110455455 C>T were detected in intron 17 and a synonymous SNP rs110256520 C>A in exon 18. It was observed that the three SNPs were in strong linkage disequilibrium (LD) with each other and therefore had the same genotype and allele frequencies. The three SNPs were found to be highly linked in one haplotype block. This haplotype block consisted of 2 haplotypes (CCA and ATG). The frequency of the CCA haplotype was 0.860 and the ATG was 0.140. Individuals of Holstein cattle tolerate heat stress to different levels. This difference between individuals may be due to variations in the genes involved in the adaptation mechanism. Therefore, it is important to identify polymorphisms in genes involved in the heat stress tolerance mechanism. In conclusion, in this study, the three SNPs and the two haplotypes were determined on the ATP1A1 gene in Turkish Holsteins cattle.

Astrocytic Glutamate Transporters and Migraine.

Glutamate levels and lifetime in the brain extracellular space are dinamically regulated by a family of Na+- and K+-dependent glutamate transporters, which thereby control numerous brain functions and play a role in numerous neurological and psychiatric diseases. Migraine is a neurological disorder characterized by recurrent attacks of typically throbbing and unilateral headache and by a global dysfunction in multisensory processing. Familial hemiplegic migraine type 2 (FHM2) is a rare monogenic form of migraine with aura caused by loss-of-function mutations in the α2 Na/K ATPase (α2NKA). In the adult brain, this pump is expressed almost exclusively in astrocytes where it is colocalized with glutamate transporters. Knockin mouse models of FHM2 (FHM2 mice) show a reduced density of glutamate transporters in perisynaptic astrocytic processes (mirroring the reduced expression of α2NKA) and a reduced rate of glutamate clearance at cortical synapses during neuronal activity and sensory stimulation. Here we review the migraine-relevant alterations produced by the astrocytic glutamate transport dysfunction in FHM2 mice and their underlying mechanisms, in particular regarding the enhanced brain susceptibility to cortical spreading depression (the phenomenon that underlies migraine aura and can also initiate the headache mechanisms) and the enhanced algesic response to a migraine trigger.

The ATP1A1 Gene Polymorphisms in Indonesian Beef Cattle

In this research, the direct sequencing method was used to identify the polymorphism and genetic diversity of the ATP1A1 gene in Indonesian beef cattle. The study used five breeds of local beef cattle with a total of 60 DNA samples (POGASI = 20, Jabres = 10, Bali = 10, Galekan = 10, and Madura = 10). The amplification of the ATP1A1 gene was using one set of primers (F = 5′- AGG GGT AGC CAG AGT TCC TA – 3′ and R = 5′ – CCC AAA GGT CAC GTG CTT TT – 3′). The result showed 6 SNPs in the APT1A1 gene, namely SNPs g.17293G/A, g.17356C/T, g.17359G/A, g.17541A/G, g.17585 A/G, and g. 17682C/T. Three SNPs were located in coding sequence nine, and the other SNPs were in intron 9 of the ATP1A1 gene. Based on the total population, the Chi-square test indicated that only two polymorphic loci (.17585 A/G and g. 17682C/T) fitted Hardy-Weinberg equilibrium (χ2<5.99). In conclusion, the polymorphic loci of the ATP1A1 gene can be used for genetic diversity and further association study to anti-heat stress traits of Indonesian beef cattle.