title: Absence of Hikeshi, a nuclear transporter for heat-shock protein HSP70, causes infantile hypomyelinating leukoencephalopathy.
abstract: Genetic leukoencephalopathies are a heterogeneous group of central nervous system disorders with white matter involvement. In a Finnish patient, we identified a novel homozygous disease-causing variant in HIKESHI, c.11G>C, p.(Cys4Ser), leading to hypomyelinating leukoencephalopathy with periventricular cysts and vermian atrophy. A founder Ashkenazi-Jewish disease-causing variant recently linked Hikeshi and its heat-shock protective function to leukoencephalopathy. In our patient, clinical features of lower limb spasticity, optic atrophy, nystagmus, and severe developmental delay were similar to reported patients. Additional features included vermian atrophy, epileptic seizures, and an ovarian tumor. Structural modeling and protein analyses revealed that modified interactions inside Hikeshi's hydrophobic pockets induce protein instability. The patient's cells showed impaired nuclear translocation of HSP70 during heat shock, and decreased ERO1-Lα, an endoplasmic reticulum (ER) oxidoreductase. Overall, we show that: (1) the clinical spectrum associated with Hikeshi deficiency extends to leukoencephalopathy with vermian atrophy and epilepsy; (2) the cellular disease process involves both nuclear chaperone and ER functions.
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Catalina
authors.initials: C
authors.lastname: Vasilescu
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.|Department of Pediatric Neurology, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Pirjo
authors.initials: P
authors.lastname: Isohanni
authors.affiliation: Department of Radiology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Maarit
authors.initials: M
authors.lastname: Palomäki
authors.affiliation: Department of Pediatric Neurology, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Helena
authors.initials: H
authors.lastname: Pihko
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.|Department of Neurology, Helsinki University Hospital and Clinical Neurosciences, University of Helsinki, Helsinki, Finland.|Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Anu
authors.initials: A
authors.lastname: Suomalainen
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Carroll
mesh_terms: D021581:Active Transport, Cell Nucleus; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics*; D002467:Cell Nucleus; D002478:Cells, Cultured; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D007223:Infant; D008562:Membrane Glycoproteins / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D055550:Protein Stability
chemical_list: D002352:Carrier Proteins; D018840:HSP70 Heat-Shock Proteins; D008562:Membrane Glycoproteins; C572913:hikeshi protein, human; C405327:ERO1A protein, human; D010088:Oxidoreductases