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Genetic reduction of the ?1 subunit of Na/K-ATPase corrects multiple hippocampal phenotypes in Angelman syndrome.

ABSTRACT: Angelman syndrome (AS) is associated with symptoms that include autism, intellectual disability, motor abnormalities, and epilepsy. We recently showed that AS model mice have increased expression of the alpha1 subunit of Na/K-ATPase (?1-NaKA) in the hippocampus, which was correlated with increased expression of axon initial segment (AIS) proteins. Our developmental analysis revealed that the increase in ?1-NaKA expression preceded that of the AIS proteins. Therefore, we hypothesized that ?1-NaKA overexpression drives AIS abnormalities and that by reducing its expression these and other phenotypes could be corrected in AS model mice. Herein, we report that the genetic normalization of ?1-NaKA levels in AS model mice corrects multiple hippocampal phenotypes, including alterations in the AIS, aberrant intrinsic membrane properties, impaired synaptic plasticity, and memory deficits. These findings strongly suggest that increased expression of ?1-NaKA plays an important role in a broad range of abnormalities in the hippocampus of AS model mice.

SUBMITTER: Kaphzan H

PROVIDER: S-EPMC3756897 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Genetic reduction of the α1 subunit of Na/K-ATPase corrects multiple hippocampal phenotypes in Angelman syndrome.

Kaphzan Hanoch H Buffington Shelly A SA Ramaraj Akila B AB Lingrel Jerry B JB Rasband Matthew N MN Santini Emanuela E Klann Eric E

Cell reports 20130801 3

Angelman syndrome (AS) is associated with symptoms that include autism, intellectual disability, motor abnormalities, and epilepsy. We recently showed that AS model mice have increased expression of the alpha1 subunit of Na/K-ATPase (α1-NaKA) in the hippocampus, which was correlated with increased expression of axon initial segment (AIS) proteins. Our developmental analysis revealed that the increase in α1-NaKA expression preceded that of the AIS proteins. Therefore, we hypothesized that α1-NaKA ...[more]

PMID: 23911285

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Project description:Angelman syndrome (AS) is a severe neurobehavioural disorder caused by defects in the maternally derived imprinted domain located on 15q11-q13. Most patients acquire AS by one of five mechanisms: (1) a large interstitial deletion of 15q11-q13; (2) paternal uniparental disomy (UPD) of chromosome 15; (3) an imprinting defect (ID); (4) a mutation in the E3 ubiquitin protein ligase gene (UBE3A); or (5) unidentified mechanism(s). All classical patients from these classes exhibit four cardinal features, including severe developmental delay and/or mental retardation, profound speech impairment, a movement and balance disorder, and AS specific behaviour typified by an easily excitable personality with an inappropriately happy affect. In addition, patients can display other characteristics, including microcephaly, hypopigmentation, and seizures.We restricted the present study to 104 patients (93 families) with a classical AS phenotype. All of our patients were evaluated for 22 clinical variables including growth parameters, acquisition of motor skills, and history of seizures. In addition, molecular and cytogenetic analyses were used to assign a molecular class (I-V) to each patient for genotype-phenotype correlations.In our patient repository, 22% of our families had normal DNA methylation analyses along 15q11-q13. Of these, 44% of sporadic patients had mutations within UBE3A, the largest percentage found to date. Our data indicate that the five molecular classes can be divided into four phenotypic groups: deletions, UPD and ID patients, UBE3A mutation patients, and subjects with unknown aetiology. Deletion patients are the most severely affected, while UPD and ID patients are the least. Differences in body mass index, head circumference, and seizure activity are the most pronounced among the classes.Clinically, we were unable to distinguish between UPD and ID patients, suggesting that 15q11-q13 contains the only significant maternally expressed imprinted genes on chromosome 15.

Dataset Information

Genetic reduction of the ?1 subunit of Na/K-ATPase corrects multiple hippocampal phenotypes in Angelman syndrome.

Publications

Genetic reduction of the α1 subunit of Na/K-ATPase corrects multiple hippocampal phenotypes in Angelman syndrome.

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