HIKESHI
protein-codingheat shock protein nuclear import factor hikeshi
Gene summary
This gene encodes an evolutionarily conserved nuclear transport receptor that mediates heat-shock-induced nuclear import of 70 kDa heat-shock proteins (Hsp70s) through interactions with FG-nucleoporins. The protein mediates transport of the ATP form but not the ADP form of Hsp70 proteins under conditions of heat shock stress. Structural analyses demonstrate that the protein forms an asymmetric homodimer and that the N-terminal domain consists of a jelly-roll/beta-sandwich fold structure that contains hydrophobic pockets involved in FG-nucleoporin recognition. Reduction of RNA expression levels in HeLa cells using small interfering RNAs results in inhibition of heat shock-induced nuclear accumulation of Hsp70s, indicating a role for this gene in regulation of Hsp70 nuclear import during heat shock stress. [provided by RefSeq, Apr 2016]
- C11orf73
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~43.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014813
Submitter: ClinGen
HIKESHI was first reported in relation to autosomal recessive hypomyelinating leukodystrophy-13 (OMIM: 616881) in 2016 (Edvardson et al., PMID: 26545878). Hikeshi protein function is essential to cell viability in conditions of heat stress and mediates the heat stress-induced nuclear import of heat shock protein (Hsp70) through a nuclear pore complex (Helman et al 2021, PMID: 34111619). This disease is clinically characterized by early onset global developmental delay, hypotonia evolving to dystonia or spastic quadriplegia, intellectual disability, and additional variable findings including neurodevelopmental regression, failure to thrive, ocular/visual abnormalities, and microcephaly (PMID: 34111619). Neuroimaging shows diffuse hypomyelination and thin corpus callosum (PMID: 34111619). Three unique missense variants that have been reported in the homozygous state in twelve probands across five publications are included in this curation (PMIDs: 26545878, 28000699, 31912665, 34111619, 38922739). All three missense variants have supporting functional data. Of note, one variant (c.160C>G (p.Val54Leu)) was observed in 10 probands of Ashkenazi Jewish descent and is likely a founder variant in this population. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by an animal model. HIKESHI conditional knockout mice displayed a reduced number of myelinated axons when compared to wildtype mice, as well as decreased thickness of the myelin (PMID: 37865085). These characteristics resemble the human phenotype of hypomyelination. In summary, there is definitive evidence supporting the relationship between HIKESHI and autosomal recessive hypomyelinating leukodystrophy-13 (MONDO:0014813), also known as HIKESHI-related hypomyelinating leukodystrophy. 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 Leukodystrophy and Leukoencephalopathy GCEP on the meeting date October 9, 2024 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0044642
Submitter: Illumina
Inheritance Pattern: AR
Disease ID:MONDO:0014813
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014813
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; 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 HIKESHI variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_016401.4. 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 | 17 | 2 | 19 | |||
| missense | 3 | 17 | 1 | 21 | ||
| nonsense | 1 | 1 | 2 | |||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 6 | 18 | 18 | 2 | 44 |
Highest pathogenic variant AF is 0.0000892378
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_057485.2 | 5 | MANE Select | |
| Ensembl | ENSP00000278483.3 | 5 | MANE Select | |
| RefSeq | NP_001309333.1 | 5 | Standard | |
| RefSeq | NP_001309336.1 | 4 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Regulation of HSF1-mediated heat shock response
- Cellular responses to stress
- Cellular responses to external stimuli
- Cellular response to heat stress
Biological Process
- protein import into nucleus
- Golgi organization
- protein transport
- lung development
- cellular response to heat
Molecular Function
- protein transporter activity
- Hsp70 protein binding
Cellular Component
- nucleus
- nucleoplasm
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000278483
- Coding exons
- 5
- Length
- 43717
- Individuals with no LoFs
- 125725
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 12
- Defined
- 125737
- p
- 0.0000477
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.933 | 75 | 101 | 0.739 | 0.00000462 | 1286 |
| Missense (PolyPhen) | 24 | 32.706 | 0.7338 | 439 | ||
| Synonymous | 0.425 | 32 | 35.2 | 0.909 | 0.00000167 | 377 |
| Loss of Function | 2.46 | 2 | 10.7 | 0.188 | 5.38e-7 | 122 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000093 | 0.000092 | rare |
| European (Non-Finnish) | 0.000071 | 0.000070 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Acts as a specific nuclear import carrier for HSP70 proteins following heat-shock stress: acts by mediating the nucleoporin-dependent translocation of ATP-bound HSP70 proteins into the nucleus. HSP70 proteins import is required to protect cells from heat shock damages. Does not translocate ADP-bound HSP70 proteins into the nucleus. {ECO:0000269|PubMed:22541429}.;
- Disease
- DISEASE: Leukodystrophy, hypomyelinating, 13 (HLD13) [MIM:616881]: An autosomal recessive neurodegenerative disorder with infantile onset, affecting mainly the central white matter. Clinical features include early feeding difficulties, global developmental delay, postnatal progressive microcephaly, truncal hypotonia, spasticity, and variable neurologic deficits, such as visual impairment. {ECO:0000269|PubMed:26545878}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.113
Intolerance Scores
- RVIS EVS
- 0.04
- RVIS percentile EVS
- 56.64
Essentials
- Essential (gene trap)
- N