INPP5D
inositol polyphosphate-5-phosphatase D
This gene is a member of the inositol polyphosphate-5-phosphatase (INPP5) family and encodes a protein with an N-terminal SH2 domain, an inositol phosphatase domain, and two C-terminal protein interaction domains. Expression of this protein is restricted to hematopoietic cells where its movement from the cytosol to the plasma membrane is mediated by tyrosine phosphorylation. At the plasma membrane, the protein hydrolyzes the 5' phosphate from phosphatidylinositol (3,4,5)-trisphosphate and inositol-1,3,4,5-tetrakisphosphate, thereby affecting multiple signaling pathways. The protein is also partly localized to the nucleus, where it may be involved in nuclear inositol phosphate signaling processes. Overall, the protein functions as a negative regulator of myeloid cell proliferation and survival. Mutations in this gene are associated with defects and cancers of the immune system. Deficiencies in the encoded protein, SHIP1, have been associated with Inflammatory Bowel Disease types such as Crohn's Disease and Ulcerative Colitis. Alternative splicing of this gene results in multiple transcript variants.
provided by RefSeq
Biological Domains
Apoptosis, Immune Response, Lipid Metabolism, Structural Stabilization
Pharos Class
Tbio
Also known as
ENSG00000168918 (Ensembl Release 114)
UNIPROTKB Q92835
SHIP, SHIP-1, SHIP1, SIP-145, hp51CN, p150Ship
Summary of Evidence
This tab shows an overview of how the selected gene is associated with AD.
Genetic Association with LOAD
Indicates whether or not this gene shows significant genetic association with Late Onset AD (LOAD) based on evidence from multiple studies compiled by the ADSP Gene Verification CommitteeTrueBrain eQTL
Indicates whether or not this gene locus has a significant expression Quantitative Trait Locus (eQTL) based on an AMP-AD consortium studyTrueRNA Expression Change in AD Brain
Indicates whether or not this gene shows significant differential expression in at least one brain region based on AMP-AD consortium work. See ‘EVIDENCE’ tab.TrueProtein Expression Change in AD Brain
Indicates whether or not this gene shows significant differential protein expression in at least one brain region based on AMP-AD consortium work. See ‘EVIDENCE’ tab.FalseNominated Target
Indicates whether or not this gene has been submitted as a nominated target to Agora.True
AD Risk Scores
About AD Risk Scores
The TREAT-AD Center at Emory-Sage-SGC has developed a Target Risk Score (TRS) to objectively rank the potential involvement of specific genes in AD. The TRS is derived by summing two component risk scores, the Genetic Risk Score and the Multi-omic Risk Score, each of which is derived from a meta-analysis of multiple harmonized data sets. More information about the methodology used to define these risk scores is available here.
AD Risk Scores for INPP5D
The TRS for INPP5D, along with the component Genetic and Multi-omic Risk Scores, is shown here. The scores for INPP5D are superimposed on the genome-wide score distributions. If No Data is Currently Available is displayed for a score, that score was not calculated for INPP5D.
Biological Domain Classification
About Biological Domains
A biological domain represents a standardized area of biology defined by a set of discrete, biologically coherent GO terms. The TREAT-AD Center at Emory-Sage-SGC has defined nineteen biological domains associated with AD, and objectively mapped genes to those biological domains using GO term annotations. More information about the methodology used to define AD biological domains, and to generate genome-wide biological domain mappings, is available here.
Biological Domains for INPP5D
Select a biological domain on the left to see the list of GO terms that link INPP5D to it on the right. The percentage value displayed next to the currently selected biological domain indicates the proportion of INPP5D's total unique GO terms that map to the biological domain. The ratio displayed on the right indicates how many of the biological domain's total GO terms INPP5D is annotated with.
RNA Expression
The results shown on this page are derived from a harmonized RNA-seq analysis of post-mortem brains from AD cases and controls. The samples were obtained from three human cohort studies across a total of nine different brain regions.
Overall Expression of INPP5D Across Brain Regions
This plot depicts the median expression of the selected gene across brain regions, as measured by RNA-seq read counts per million (CPM) reads. Meaningful expression is considered to be a log2 CPM greater than log2(5), depicted by the red line in the plot.
Filter the following charts by statistical model
Differential Expression of INPP5D Across Brain Regions
After selecting a statistical model, you will be able to see whether the selected gene is differentially expressed between AD cases and controls. The box plot depicts how the differential expression of the selected gene of interest (purple dot) compares with expression of other genes in a given tissue. Summary statistics for each tissue can be viewed by hovering over the purple dots. Meaningful differential expression is considered to be a log2 fold change value greater than 0.263, or less than -0.263.
Consistency of Change in Expression
This forest plot indicates the estimate of the log fold change with 95% confidence interval across the brain regions in the model chosen using the filter above. Genes that show consistent patterns of differential expression will have similar log-fold change value across brain regions.
Correlation of INPP5D with Hallmarks of AD
This plot depicts the association between expression levels of the selected gene in the DLPFC and three phenotypic measures of AD. An odds ratio > 1 indicates a positive correlation and an odds ratio < 1 indicates a negative correlation. Statistical significance and summary statistics for each phenotype can be viewed by hovering over the dots.
Similarly Expressed Genes
The network diagram below is based on a coexpression network analysis of RNA-seq data from AD cases and controls. The network analysis uses an ensemble methodology to identify genes that show similar coexpression across individuals.
The color of the edges and nodes indicates how frequently significant coexpression was identified. Each node represents a different gene and the amount of edges within the network. Darker edges represent coexpression in more brain regions.
Proteomics
Proteomic analyses of post-mortem brains show whether protein products of INPP5D are differentially expressed between AD cases and controls. Each box plot depicts how the differential expression of the protein(s) of interest (purple dot) compares with expression of other proteins in a given brain region. Summary statistics for each tissue can be viewed by hovering over the purple dots.
Targeted SRM Differential Protein Expression
Selected Reaction Monitoring (SRM) data was generated from the DLPFC region of post-mortem brains of over 1000 individuals from multiple human cohort studies.
Note that only a single SRM result is available for a given gene, as the probes used for this experiment were designed to match multiple protein products derived from each targeted gene.
Genome-wide Differential Protein Expression
Select a protein from the dropdown menu to see whether it is differentially expressed between AD cases and controls.
The assay-specific box plots below depict how the differential expression of the selected protein of interest (purple dot) compares with expression of other proteins in each brain region that was assayed. Assay-specific summary statistics for each brain region can be viewed by hovering over the purple dot.
Multiple proteins may map to a single gene. Results from both TMT and LFQ assays are provided, however results for some proteins may be available for only one of the assays.
TMT Differential Protein Expression
Tandem mass tagged (TMT) data was generated from the DLPFC region of post-mortem brains of 400 individuals from the ROSMAP cohort.
Note that proteins may not be detected in this brain region; for these proteins, the plot will show no data.
LFQ Differential Protein Expression
Liquid-free quantification (LFQ) data was generated from post-mortem brains of more than 500 individuals. Samples were taken from four human cohort studies, representing four different brain regions.
Note that proteins may not be detected in all four brain regions; for these proteins, the plot will show fewer than four brain regions.
Metabolomics
The results shown on this page are derived from an analysis of metabolite levels from AD cases and controls. The samples were obtained from approximately 1400 individuals from the ADNI study. Metabolites are associated with genes using genetic mapping and the metabolite with the highest genetic association is shown for each gene.
Mapping of Metabolites to INPP5D
Genetic mapping revealed that the top metabolite associated with INPP5D is Glycochenodeoxycholate, with a p-value of 0.0000089.
Levels of Glycochenodeoxycholate by Disease Status
This plot shows differences in metabolite levels in AD cases (AD) and cognitively-normal individuals (CN). This comparison is significantly different with a p-value of 0.038.
Target Enabling Resources
Use these links to discover the Target Enabling Resources for INPP5D that are currently available, under development, or planned.
Drug Development Resources
These external sites provide information and resources related to drug development.
Additional Resources
These external sites provide additional information about therapeutic targets for AD and related dementias.
Evidence Supporting the Nomination of INPP5D
This gene has been nominated as a potential target for AD. Nominated targets are obtained from several sources, including the National Institute on Aging's Accelerating Medicines Partnership in Alzheimer's Disease (AMP-AD) consortium. Targets have been identified using computational analyses of high-dimensional genomic, proteomic and/or metabolomic data derived from human samples.
AMP-AD: Duke University
The Duke AMP-AD team, led by Rima Kaddurah-Daouk, focuses on taking an integrated metabolomics-genetics-imaging systems approach to define network failures in Alzheimer's disease.
Why was the target selected?
AD atlas shows overlapping associations of AD (genome-wide significant) and several bile acids that are associated with AD endophenotypes, as well as associations with the CSF tau/Abeta ratio. Population-based studies replicate the association with the bile acid taurochenodeoxycholate. This gene is a member of the inositol polyphosphate-5-phosphatase (INPP5) family and encodes a protein with an N-terminal SH2 domain, an inositol phosphatase domain, and two C-terminal protein interaction domains. Expression of this protein is restricted to hematopoietic cells where its movement from the cytosol to the plasma membrane is mediated by tyrosine phosphorylation. At the plasma membrane, the protein hydrolyzes the 5' phosphate from phosphatidylinositol (3,4,5)-trisphosphate and inositol-1,3,4,5-tetrakisphosphate, thereby affecting multiple signaling pathways. The protein is also partly localized to the nucleus, where it may be involved in nuclear inositol phosphate signaling processes. Overall, the protein functions as a negative regulator of myeloid cell proliferation and survival.
Predicted therapeutic direction
Unknown.
The type of data used and analyses done to identify target
Metabolic pathway association analysis (by partial correlations and mining of metabolic knowledgebases), coupled with metabolite GWAS analyses, mining of eQTL, PPI, and protein databases, as well as manual textmining
Cohort study data: ADNI
Initial date of nomination
2018
Planned Experimental Validation
not prioritized for experimental validation
Learn more about the target nomination processAMP-AD: The Mayo Clinic - University of Florida - The Institute for Systems Biology
The Mayo-UFL-ISB AMP-AD team, led by Nilufer Ertekin-Taner, Todd Golde, Nathan Price, and Steven Younkin, includes three institutions: the University of Florida, the Institute for Systems Biology, and the Mayo Clinic Jacksonville. The focus of the team is to identify therapeutic targets within the innate immune signaling cascade in Alzheimer's disease that can be safely manipulated to provide disease modification.
Why was the target selected?
A key regulator of inhibitory immune signaling. Druggable. Implicated by genetics in AD.
Predicted therapeutic direction
Antagonism predicted to reduce disease progression.
The type of data used and analyses done to identify target
A logical target to disinhibit immune activation in the brain. We are not pursuing directly. Given tools in pharma a great target for them.
Cohort study data: Mayo
Initial date of nomination
2018
Planned Experimental Validation
not prioritized for experimental validation
Learn more about the target nomination processAMP-AD: The Zhang Lab at the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai AMP-AD team lead by Eric Schadt, Bin Zhang, Jun Zhu, Michelle Ehrlich, Vahram Haroutunian, Samuel Gandy, Koichi Iijima, and Scott Noggle focuses on developing a multiscale network approach to elucidating the complexity of Alzheimer's disease.
Why was the target selected?
INPP5D was up-regulated in the parahippocampal area of CERAD definite AD brains. It was identified as an important key driver in the Bayesian network analysis and it is also an AD GWAS candidate.
Predicted therapeutic direction
Antagonism predicted to reduce disease progression. INPP5D was significantly up-regulated in the parahippocampal area of CERAD definite AD (adjusted p=1.08x10^-5, FC=1.33) / Demented (adjusted p=4.01x10^-3, FC=1.27) / severely Plaqued (adjusted p=1.94x10^-4, FC=1.36) brains compared to the controls.
The type of data used and analyses done to identify target
Bayesian network analysis derived from RNAseq and WGS genotypes.
Cohort study data: MSBB
Initial date of nomination
2018
Planned Experimental Validation
validation studies ongoing
Learn more about the target nomination processTREAT-AD: The Indiana University School of Medicine (IUSM) - Purdue
At the Indiana University School of Medicine (IUSM)-Purdue TREAT-AD center, our strategic goal is to integrate sophisticated capability for early drug discovery and contribute to a broader study of emerging Alzheimer's Disease (AD) target hypotheses and etiologies with the goal of generating new classes of potential therapeutics. Specifically, the group will establish itself as a strategic and operational partner for the National Institute on Aging (NIA) Accelerating Medicines Partnership-Alzheimer's Disease (AMP-AD) and Model Organism Development and Evaluation for Late Onset Alzheimer's Disease (MODEL-AD) initiatives. By design, this will provide drug discovery capability to bridge the foundational work in target discovery (AMP-AD) with newly discovered lead molecules characterized in AD animal models based on human pathology, genetics, and translational biomarkers (MODEL-AD). A key advantage and differentiated strength of the Center is the primary scientific coordination and administration through the Indiana University School of Medicine. Specifically, this concentrates a strong and long-standing commitment to neurodegenerative research through co-presence with the NIA-supported Indiana Alzheimer's Disease Center, the MODEL-AD consortium, and the Longitudinal Early Onset Alzheimer's Disease (LEAD) study.
Why was the target selected?
By applying the algorithm and process developed in https://doi.org/10.1038/s41598-020-79740-x, we identified frequently co-expressed gene modules
Predicted therapeutic direction
Antagonism predicted to reduce disease progression. Elevated in AD brain transcriptomic data; Frequently coexpressed in microglia core module from AD transcriptomic data
The type of data used and analyses done to identify target
AD and normal brain transcriptomic datasets
Cohort study data: GSE5281, GSE48350, GSE33000, GSE44772, ROSMAP, MSBB, Mayo, ABA
Initial date of nomination
2022
Planned Experimental Validation
validation studies completed
Experimental Validation of INPP5D
Nominating teams provided details on experimental validation studies they performed to examine a role for the target in AD.
AMP-AD : The Zhang Lab at the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai AMP-AD team lead by Eric Schadt, Bin Zhang, Jun Zhu, Michelle Ehrlich, Vahram Haroutunian, Samuel Gandy, Koichi Iijima, and Scott Noggle focuses on developing a multiscale network approach to elucidating the complexity of Alzheimer's disease.
Hypothesis Being Tested
Modulating expression of INPP5D in microglia and astrocytes will alter AD subnetworks and cell type specific functions in INPP5D KO iPSC lines and isogenic controls and in INPP5D germline KO and microglia specific KO mouse models.
Species and Model System
Human, Mouse; iPSC-derived microglia, iPSC-astrocytes, INPP5D KO mice (germ-line CMV-Cre & Tamoxifen inducible Cx3CR1-Cre ERT)
Outcome Measure
Other; Multiple outcome measures including: bulk RNAseq analysis and functional analysis of microglia from ko vs wt; analysis of iPSC-astrocyte differentiation and function and comparison with ko mouse models (balanced for sex)
Summary of Findings
Studies in progress
Contributors
Davide Marotta, Valentina Fossati, Scott Noggle, Michelle Ehrlich, Emilie Castranio
Published?
No
Date of Report
12/1/20
AMP-AD : The Zhang Lab at the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai AMP-AD team lead by Eric Schadt, Bin Zhang, Jun Zhu, Michelle Ehrlich, Vahram Haroutunian, Samuel Gandy, Koichi Iijima, and Scott Noggle focuses on developing a multiscale network approach to elucidating the complexity of Alzheimer's disease.
Hypothesis Being Tested
INPP5D expression or its protein activity plays a role in AD pathophysiology.
Species and Model System
Mouse; PSAPP mice
Outcome Measure
Immunochemistry; Abeta fibrillization, plaque burden, phagocytosis
Summary of Findings
By inducing Inpp5d knockdown in microglia of PSAPP mice, we found that the percent area of 6E10+ deposits and plaque-associated microglia in Inpp5d knockdown mice were increased compared to controls. Spatial transcriptomics identified a plaque-specific expression profile that was extensively altered by Inpp5d knockdown.
Contributors
Emilie L. Castranio, Philip Hasel, Jean-Vianney Haure-Mirande, Angie V. Ramirez Jimenez, B. Wade Hamilton, Rachel D. Kim, Charles G. Glabe, Minghui Wang, Bin Zhang, Sam Gandy, Shane A. Liddelow, Michelle E. Ehrlich
Published?
Yes; https://doi.org/10.1002/alz.12821
Date of Report
12/1/23