Last update 01 Nov 2024

SLC9A7

Last update 01 Nov 2024

Basic Info

Synonyms

Na(+)/H(+) exchanger 7, NHE-7, NHE7

+ [7]

Introduction

Golgi Na(+), K(+)/(H+) antiporter. Mediates the electoneutral influx of Na(+) or K(+) in exchange for H(+). May contribute to the regulation of Golgi apparatus volume and pH.

Drugs associated with SLC9A7

d9A-2

Target

NHE1 x NHE2 x SLC9A4 x SLC9A7 x SLC9B1

Mechanism

NHE1 inhibitors [+4]

Active Org.

Das CeMM - Forschungszentrum für Molekulare Medizin GmbH

Originator Org.-

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with SLC9A7

100 Translational Medicine associated with SLC9A7

0 Patents (Medical) associated with SLC9A7

Literatures (Medical) associated with SLC9A7

01 Oct 2024·JAMA Neurology

Role of the X Chromosome in Alzheimer Disease Genetics

Article

Author: Herz, Joachim ; Greicius, Michael D. ; Merritt, Victoria ; Sherva, Richard ; Napolioni, Valerio ; Panizzon, Matthew S. ; Stewart, Ilaria ; Belloy, Michael E. ; Hauger, Richard L. ; Zhang, Rui ; Le Guen, Yann ; Gaziano, J. Michael ; Logue, Mark ; Williams, Kennedy

ImportanceThe X chromosome has remained enigmatic in Alzheimer disease (AD), yet it makes up 5% of the genome and carries a high proportion of genes expressed in the brain, making it particularly appealing as a potential source of unexplored genetic variation in AD.ObjectivesTo perform the first large-scale X chromosome–wide association study (XWAS) of AD.Design, Setting, and ParticipantsThis was a meta-analysis of genetic association studies in case-control, family-based, population-based, and longitudinal AD-related cohorts from the US Alzheimer’s Disease Genetics Consortium, the Alzheimer’s Disease Sequencing Project, the UK Biobank, the Finnish health registry, and the US Million Veterans Program. Risk of AD was evaluated through case-control logistic regression analyses. Data were analyzed between January 2023 and March 2024. Genetic data available from high-density single-nucleotide variant microarrays and whole-genome sequencing and summary statistics for multitissue expression and protein quantitative trait loci available from published studies were included, enabling follow-up genetic colocalization analyses. A total of 1 629 863 eligible participants were selected from referred and volunteer samples, 477 596 of whom were excluded for analysis exclusion criteria. The number of participants who declined to participate in original studies was not available.Main Outcome and MeasuresRisk of AD, reported as odds ratios (ORs) with 95% CIs. Associations were considered at X chromosome–wide (P &lt; 1 × 10−5) and genome-wide (P &lt; 5 × 10−8) significance. Primary analyses are nonstratified, while secondary analyses evaluate sex-stratified effects.ResultsAnalyses included 1 152 284 participants of non-Hispanic White, European ancestry (664 403 [57.7%] female and 487 881 [42.3%] male), including 138 558 individuals with AD. Six independent genetic loci passed X chromosome–wide significance, with 4 showing support for links between the genetic signal for AD and expression of nearby genes in brain and nonbrain tissues. One of these 4 loci passed conservative genome-wide significance, with its lead variant centered on an intron of SLC9A7 (OR, 1.03; 95% CI, 1.02-1.04) and colocalization analyses prioritizing both the SLC9A7 and nearby CHST7 genes. Of these 6 loci, 4 displayed evidence for escape from X chromosome inactivation with regard to AD risk.Conclusion and RelevanceThis large-scale XWAS of AD identified the novel SLC9A7 locus. SLC9A7 regulates pH homeostasis in Golgi secretory compartments and is anticipated to have downstream effects on amyloid β accumulation. Overall, this study advances our knowledge of AD genetics and may provide novel biological drug targets. The results further provide initial insights into elucidating the role of the X chromosome in sex-based differences in AD.

01 Aug 2024·Journal of Biological Chemistry

GGA1 interacts with the endosomal Na+/H+ exchanger NHE6 governing localization to the endosome compartment

Article

Author: Morrow, Eric M ; Ouyang, Qing ; Ma, Li ; Schmidt, Michael ; Kasula, Ravi Kiran

Mutations in the endosomal Na+/H+ exchanger 6 (NHE6) cause Christianson syndrome, an X-linked neurological disorder. NHE6 functions in regulation of endosome acidification and maturation in neurons. Using yeast two-hybrid screening with the NHE6 carboxyl terminus as bait, we identify Golgi-associated, gamma adaptin ear-containing, ADP-ribosylation factor (ARF) binding protein 1 (GGA1) as an interacting partner for NHE6. We corroborated the NHE6-GGA1 interaction using: coimmunoprecipitation; overexpressed constructs in mammalian cells; and coimmunoprecipitation of endogenously expressed GGA1 and NHE6 from neuroblastoma cells, as well as from the mouse brain. We demonstrate that GGA1 interacts with organellar NHEs (NHE6, NHE7, and NHE9) and that there is significantly less interaction with cell-surface localized NHEs (NHE1 and NHE5). By constructing hybrid NHE1/NHE6 exchangers, we demonstrate the cytoplasmic tail of NHE6 interacts most strongly with GGA1. We demonstrate the colocalization of NHE6 and GGA1 in cultured, primary hippocampal neurons, using super-resolution microscopy. We test the hypothesis that the interaction of NHE6 and GGA1 functions in the localization of NHE6 to the endosome compartment. Using subcellular fractionation experiments, we show that NHE6 is mislocalized in GGA1 KO cells, wherein we find less NHE6 in endosomes, but more NHE6 transport to lysosomes, and more Golgi retention of NHE6, with increased exocytosis to the surface plasma membrane. Consistent with NHE6 mislocalization, and Golgi retention, we find the intraluminal pH in Golgi to be alkalinized in GGA1-null cells. Our study demonstrates a new interaction between NHE6 and GGA1 which functions in the localization of this intracellular NHE to the endosome compartment.

10 Jun 2024·Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics

[Clinical and genetic analysis of a child with X-linked mental retardation due to variant of SLC9A7 gene].

Article

Author: Tamang, Spana ; Wang, Huaili ; Li, Wei ; Fu, Tianjiao ; Wang, Yao ; Zhuo, Zhihong

OBJECTIVETo explore the clinical and genetic characteristics of a child with mental retardation, language and motor developmental delay and epilepsy.METHODSA child who was admitted to the First Affiliated Hospital of Zhengzhou University in March 2020 for intermittent seizures for over two months was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples of the child and his parents were collected and subjected to high throughput sequencing. Candidate variants were verified by Sanger sequencing and bioinformatic analysis.RESULTSThe clinical manifestations of the child have included mental retardation, language and motor developmental delay, and seizures. High-throughput sequencing revealed that he has harbored a hemizygous splice site variant (NM_032591.3: c.1030-1G>C) of the SLC9A7 gene, which was inherited from his mother and unreported previously.CONCLUSIONThe hemizygous splice site variant (NM_032591.3: c.1030-1G>C) of the SLC9A7 gene probably underlay the disease in this child. Above finding has provided a basis for clinical diagnosis and genetic counseling.

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SLC9A7

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