title: Leukoencephalopathy and early death associated with an Ashkenazi-Jewish founder mutation in the Hikeshi gene.
abstract: BACKGROUND
  Leukodystrophies are genetic white matter disorders affecting the formation or maintenance of myelin. Among the recently discovered genetic defects associated with leukodystrophies, several genes converge on a common mechanism involving protein transcription/translation and ER stress response.
  
  
  METHODS
  The genetic basis of a novel congenital leukodystrophy, associated with early onset spastic paraparesis, acquired microcephaly and optic atrophy was studied in six patients from three unrelated Ashkenazi-Jewish families. To this end we used homozygosity mapping, exome analysis, western blot (Hikeshi, HSF1-pS326 and b-actin) in patient fibroblasts, indirect immunofluorescence (HSP70 and HSF1) in patient fibroblasts undergoing heat shock stress, nuclear injection of plasmids expressing Hikeshi or EGFP in patient fibroblasts, in situ hybridization and Immunoblot analysis of Hikeshi in newborn and adult mouse brain.
  
  
  RESULTS
  All the patients were homozygous for a missense mutation, p.Val54Leu, in C11ORF73 encoding HSP70 nuclear transporter protein, Hikeshi. The mutation segregated with the disease in the families and was carried by 1:200 Ashkenazi-Jewish individuals. The mutation was associated with undetectable level of Hikeshi in the patients' fibroblasts and with lack of nuclear HSP70 during heat shock stress, a phenomenon which was reversed upon the introduction of normal human Hikeshi to the patients cells. Hikeshi was found to be expressed in central white matter of mouse brain.
  
  
  CONCLUSIONS
  These data underscore the importance of Hikeshi for HSP70 relocation into the nucleus. It is likely that in the absence of Hikeshi, HSP70 cannot attenuate the multiple heat shock induced nuclear phenotypes, leaving the cells unprotected during heat shock stress. We speculate that the sudden death of three of the six patients following a short febrile illness and the life-threatening myo-pericarditis in the fourth are the result of excess extra-nuclear HSP70 level which initiates cytokine release or provide target for natural killer cells. Alternatively, nuclear HSP70 might play an active role in stressed cells protection.
authors.affiliation: The Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Simon
authors.initials: S
authors.lastname: Edvardson
authors.affiliation: Cellular Dynamics Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Kose
authors.affiliation: Bonei Olam, Center for Rare Jewish Genetic Disorders, Brooklyn, New York, USA.
authors.forename: Chaim
authors.initials: C
authors.lastname: Jalas
authors.affiliation: Pediatric Neurology Unit, Dana Children Hospital, Tel-Aviv Medical Center, affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Aviva
authors.initials: A
authors.lastname: Fattal-Valevski
authors.affiliation: Cellular Dynamics Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Cellular Dynamics Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Ogawa
authors.affiliation: Cellular Dynamics Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mamada
authors.affiliation: Department of Microbiology and Molecular Genetics, Rutgers-Robert Wood Johnson Medical School Piscataway, Basking Ridge, New Jersey, USA.
authors.forename: Anastasia M
authors.initials: AM
authors.lastname: Fedick
authors.affiliation: Genetic Institute, Tel-Aviv Medical Center, affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Shay
authors.initials: S
authors.lastname: Ben-Shachar
authors.affiliation: Reproductive Medicine Associates of New Jersey Basking Ridge, Basking Ridge, New Jersey, USA.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Treff
authors.affiliation: The Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Avraham
authors.initials: A
authors.lastname: Shaag
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Sherri
authors.initials: S
authors.lastname: Bale
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics and Adolescent Medicine, University Medical Center, Göttingen, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Gärtner
authors.affiliation: Cellular Dynamics Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Imamoto
authors.affiliation: The Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
mesh_terms: D000293:Adolescent; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002675:Child, Preschool; D005260:Female; D018703:Founder Effect; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007585:Jews / Q000235:genetics*; D056784:Leukoencephalopathies / Q000235:genetics*; D008297:Male; D051379:Mice; D009154:Mutation; D015418:Optic Atrophies, Hereditary / Q000235:genetics; D010375:Pedigree
chemical_list: D002352:Carrier Proteins; D018840:HSP70 Heat-Shock Proteins; C572913:hikeshi protein, human
keywords: Neurology