HIKESHI

Chr 11AR

heat shock protein nuclear import factor hikeshi

Also known as: C11orf73, HLD13, HSPC138, HSPC179, L7RN6, OPI10

NCBI Gene: 51501 ENSG00000149196 UniProt: Q53FT3 OMIM: 614908

The protein functions as a nuclear transport receptor that specifically imports ATP-bound HSP70 heat shock proteins into the nucleus during cellular stress responses. Mutations cause hypomyelinating leukodystrophy 13, an autosomal recessive disorder affecting white matter development in the brain. This gene shows moderate constraint against loss-of-function variants (LOEUF 0.59), suggesting some tolerance to functional disruption.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.591 OMIM phenotype

Clinical Summary— HIKESHI

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Gene-Disease Validity (ClinGen)

hypomyelinating leukodystrophy 13 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.52) — some intolerance to loss-of-function variants.

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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 20 VUS of 69 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — HIKESHI

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.59LOEUF

pLI 0.525

Z-score 2.46

OE 0.19 (0.08–0.59)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.93Z-score

OE missense 0.74 (0.61–0.90)

75 obs / 101.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.19 (0.08–0.59)

0≤0.351.4

Missense OE?0.74 (0.61–0.90)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 2 / 10.7Missense obs/exp: 75 / 101.5Syn Z: 0.43

This gene — mechanism propensity

0.6357th %ile

GOF

0.5954th %ile

LOF

0.4332th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

LOF60% of P/LP variants are LoF

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

69 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic5

VUS20

Likely Benign34

Benign4

Conflicting1

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	3	2	0	0	5
VUS	2	16	2	0	20
Likely Benign	0	1	16	17	34
Benign	0	0	2	2	4
Conflicting	—				1
Total	5	19	20	19	64

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

21 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap HIKESHI — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →