MAPK8IP3
protein-codingmitogen-activated protein kinase 8 interacting protein 3, the group of MicroRNA protein coding host genes
Gene summary
The protein encoded by this gene shares similarity with the product of Drosophila syd gene, required for the functional interaction of kinesin I with axonal cargo. Studies of the similar gene in mouse suggested that this protein may interact with, and regulate the activity of numerous protein kinases of the JNK signaling pathway, and thus function as a scaffold protein in neuronal cells. The C. elegans counterpart of this gene is found to regulate synaptic vesicle transport possibly by integrating JNK signaling and kinesin-1 transport. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~64.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0032755
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0032755
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0032755
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0032755
Submitter: Illumina
The MAPK8IP3 gene was first reported in relation to autosomal dominant MAPK8IP3-related neurodevelopmental disorder with or without variable brain abnormalities in 2019 (30612693: Platzer et al. 2019). At least six unique variants (including five missense variants and one stop-gained) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least six probands in two publications (30612693: Platzer et al. 2019; 30945334: Iwasawa et al. 2019). The mechanism of the disease is not yet established. However, it is known that the protein encoded by MAPK8IP3 acts as a regulator of vesicle transport and promotes neuronal axon elongation in a kinesin- and JNK-dependent manner and that both missense variants in important functional domains and null variants are implicated in disease. This gene-disease relationship is supported by evidence from model organisms where the effect of five missense and one null variant on axonal lysosomal accumulation in C.elegans was evaluated with at least three of the variants resulting in higher axonal lysosomal density and reduced swimming rates (30612693: Platzer et al. 2019). In addition, a heterozygous knockout mouse for the MAPK8IP3 gene was shown to present with axonal lysosome accumulations demonstrating a role for the protein in axonal lysosome transport (28784610: Gowrishankar et al. 2017). In summary, there is strong evidence to support the relationship between the MAPK8IP3 gene and MAPK8IP3-related neurodevelopmental disorder with or without variable brain abnormalities (autosomal dominant). Additional reports in humans are needed over time from the first proposal of the association to reach a definitive classification.
Inheritance Pattern: AD
Disease ID:MONDO:0032755
Submitter: ClinGen
The MAPK8IP3 gene is located on chromosome 16 at 16q13.3 and encodes the Mitogen-Activated Protein Kinase 8 Interacting Protein 3, one of the family of JNK-interacting protein group of scaffold proteins. MAPK8IP3 was first reported in relation to autosomal dominant MAPK8IP3-related neurodevelopmental disorders in 2019 (Platzer et al., PMID: 30612693). 7 variants (including 4 missense, 2 nonsense, and 1 frameshift) have been reported in 9 probands in 2 publications (PMID: 30612693; Iwasawa et al., 2019, PMID: 30945334) and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of the disease is not yet established. However, it is known that the protein encoded by MAPK8IP3 acts as a regulator of vesicle transport and promotes neuronal axon elongation in a kinesin- and JNK-dependent manner. Both missense variants located in functional domains and null variants, all of which are de novo, are implicated in disease. This gene-disease relationship is also supported by experimental evidence (e.g. animal models, rescue and expression studies) (Gowrishankar et al., 2017, PMID: 28784610; PMID: 30612693). In summary, MAPK8IP3 is definitively associated with autosomal dominant MAPK8IP3-related neurodevelopmental disorder with or without variable brain abnormalities. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 10.26.2021 (SOP Version 8).
Inheritance Pattern: AD
Disease ID:MONDO:0032755
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal; Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MAPK8IP3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001318852.2. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 8 | 94 | 7 | 109 | ||
| missense | 12 | 371 | 65 | 448 | ||
| nonsense | 2 | 5 | 9 | 16 | ||
| start loss | 0 | |||||
| frameshift | 2 | 5 | 5 | 12 | ||
| splice donor/acceptor (+/-2bp) | 6 | 9 | 4 | 19 | ||
| Total | 4 | 28 | 402 | 163 | 7 | 604 |
Highest pathogenic variant AF is 0.0000021105595
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001305781.1 | 32 | MANE Select | |
| Ensembl | ENSP00000481780.1 | 32 | MANE Select | |
| RefSeq | NP_001035529.1 | 31 | Standard | |
| RefSeq | NP_055948.2 | 32 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| mapk8ip3 | Danio rerio | Structure: posterior lateral line Quality: swollen abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- MAPK signaling pathway - Homo sapiens (human)
- EGF-Ncore
- MAPK Signaling Pathway
- Arf6 trafficking events
- Signaling events mediated by focal adhesion kinase
Biological Process
- activation of JUN kinase activity
- vesicle-mediated transport
- axon regeneration
- regulation of JNK cascade
- axon development
Molecular Function
- MAP-kinase scaffold activity
- protein binding
- JUN kinase binding
- kinesin binding
- receptor signaling complex scaffold activity
Cellular Component
- Golgi membrane
- cytoplasm
- axon
- dendrite
- growth cone
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000250894
- Coding exons
- 32
- Length
- 64135
- Individuals with no LoFs
- 124732
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 48
- Defined
- 124780
- p
- 0.000192
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.88 | 663 | 908 | 0.731 | 0.0000620 | 8685 |
| Missense (PolyPhen) | 133 | 288.78 | 0.46056 | 2743 | ||
| Synonymous | -2.54 | 453 | 389 | 1.16 | 0.0000296 | 2622 |
| Loss of Function | 7.19 | 5 | 69.9 | 0.0715 | 0.00000340 | 756 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00019 | 0.00019 | rare |
| Latino/Admixed American | 0.000091 | 0.000087 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000060 | 0.000056 | rare |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.00033 | 0.00033 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0.00018 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates JNK signaling by aggregating specific components of the MAPK cascade to form a functional JNK signaling module (PubMed:12189133). May function as a regulator of vesicle transport, through interactions with the JNK-signaling components and motor proteins (By similarity). Promotes neuronal axon elongation in a kinesin- and JNK-dependent manner. Activates cofilin at axon tips via local activation of JNK, thereby regulating filopodial dynamics and enhancing axon elongation. Its binding to kinesin heavy chains (KHC), promotes kinesin-1 motility along microtubules and is essential for axon elongation and regeneration. Regulates cortical neuronal migration by mediating NTRK2/TRKB anterograde axonal transport during brain development (By similarity). Acts as an adapter that bridges the interaction between NTRK2/TRKB and KLC1 and drives NTRK2/TRKB axonal but not dendritic anterograde transport, which is essential for subsequent BDNF-triggered signaling and filopodia formation (PubMed:21775604). {ECO:0000250|UniProtKB:Q9ESN9, ECO:0000269|PubMed:12189133, ECO:0000269|PubMed:21775604}.;
Recessive Scores
- pRec
- 0.189
Intolerance Scores
- LoFtool
- 0.0583
- RVIS EVS
- -2.65
- RVIS percentile EVS
- 0.77
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.959
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |