Variant Synonymizer: Platform to identify mutations defined in different ways is available now!

VarSy

Over 2,000 gene–disease validation summaries are now available—no login required!

Browse Summaries

HIKESHI – Hypomyelinating Leukodystrophy 13

HIKESHI-associated hypomyelinating leukodystrophy 13 is inherited in an autosomal recessive manner. A single unrelated proband presented at 7 months with global developmental delay and MRI features of delayed myelination, and was homozygous for the variant c.4T>G (p.Phe2Val), which resulted in absent HIKESHI protein in fibroblasts and impaired heat-induced nuclear localization of HSP70, consistent with loss-of-function (PMID:38922739). Variant segregation was limited to parental heterozygosity without additional affected relatives.

Functional assays across multiple models corroborate the pathogenic mechanism. Rescue of HSP70 nuclear translocation by vector-mediated HIKESHI expression in patient fibroblasts confirmed loss-of-function (PMID:38922739). In mouse oligodendroglial cells, the Cys4Ser mutant mislocalized to lysosomes, interacted aberrantly with Filamin A, and inhibited morphological differentiation, reflecting disease pathology (PMID:33535532). Moreover, studies of the HIKESHI–HSP70 interaction under heat stress elucidate the nuclear import function critical for cellular stress response (PMID:38987995).

No conflicting reports have been identified. While based on a single proband, the concordant functional data support a Limited clinical validity classification. Key take-home: HIKESHI loss-of-function variants cause hypomyelinating leukodystrophy 13, and gene replacement shows promise as a therapeutic approach.

References

  • American Journal of Medical Genetics Part A • 2024 • A novel missense variant in HIKESHI: Clinical phenotype, in vitro functional testing, and potential for gene therapy. PMID:38922739
  • Medicines (Basel, Switzerland) • 2021 • The Infantile Leukoencephalopathy-Associated Mutation of C11ORF73/HIKESHI Proteins Generates de novo Interactive Activity with Filamin A, Inhibiting Oligodendroglial Cell Morphological Differentiation. PMID:33535532
  • Genes to Cells • 2024 • The interaction between the import carrier Hikeshi and HSP70 is modulated by heat, facilitating the nuclear import of HSP70 under heat stress conditions. PMID:38987995

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Single homozygous proband with no additional segregation but concordant functional data across multiple assays

Genetic Evidence

Limited

One AR proband with homozygous c.4T>G (p.Phe2Val) (PMID:38922739); no additional segregation

Functional Evidence

Moderate

Rescue of HSP70 nuclear translocation in patient fibroblasts (PMID:38922739), loss-of-function cellular phenotypes in oligodendroglial models (PMID:33535532), and mechanistic insights into HIKESHI–HSP70 import (PMID:38987995)