A recurrent de novo HSPD1 variant is associated with hypomyelinating leukodystrophy

Cold Spring Harb Mol Case Stud. 2020 Jun 12;6(3):a004879. doi: 10.1101/mcs.a004879. Print 2020 Jun.


Standardization of the use of next-generation sequencing for the diagnosis of rare neurological disorders has made it possible to detect potential disease-causing genetic variations, including de novo variants. However, the lack of a clear pathogenic relevance of gene variants poses a critical limitation for translating this genetic information into clinical practice, increasing the necessity to perform functional assays. Genetic screening is currently recommended in the guidelines for diagnosis of hypomyelinating leukodystrophies (HLDs). HLDs represent a group of rare heterogeneous disorders that interfere with the myelination of the neurons in the central nervous system. One of the HLD-related genes is HSPD1, encoding the mitochondrial chaperone heat shock protein 60 (HSP60), which functions as folding machinery for the mitochondrial proteins imported into the mitochondrial matrix space. Disease-causing HSPD1 variants have been associated with an autosomal recessive form of fatal hypomyelinating leukodystrophy (HLD4, MitCHAP60 disease; MIM #612233) and an autosomal dominant form of spastic paraplegia, type 13 (SPG13; MIM #605280). In 2018, a de novo HSPD1 variant was reported in a patient with HLD. Here, we present another case carrying the same heterozygous de novo variation in the HSPD1 gene (c.139T > G, p.Leu47Val) associated with an HLD phenotype. Our molecular studies show that the variant HSP60 protein is stably present in the patient's fibroblasts, and functional assays demonstrate that the variant protein lacks in vivo function, thus confirming its disease association. We conclude that de novo variations of the HSPD1 gene should be considered as potentially disease-causing in the diagnosis and pathogenesis of the HLDs.

Keywords: abnormal CNS myelination; cerebral hypomyelination.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adult
  • Alleles
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Chaperonin 10 / genetics
  • Chaperonin 60 / chemistry
  • Chaperonin 60 / genetics*
  • Child
  • Female
  • Genetic Association Studies* / methods
  • Genetic Predisposition to Disease*
  • Genetic Variation*
  • Genotype
  • Hereditary Central Nervous System Demyelinating Diseases / diagnosis*
  • Hereditary Central Nervous System Demyelinating Diseases / genetics*
  • Humans
  • Infant
  • Magnetic Resonance Imaging
  • Male
  • Mitochondrial Diseases / diagnosis*
  • Mitochondrial Diseases / genetics*
  • Mitochondrial Proteins / chemistry
  • Mitochondrial Proteins / genetics*
  • Models, Molecular
  • Mutation
  • Pregnancy Proteins / genetics
  • Protein Conformation
  • Recurrence
  • Structure-Activity Relationship
  • Suppressor Factors, Immunologic / genetics


  • Chaperonin 10
  • Chaperonin 60
  • HSPD1 protein, human
  • Mitochondrial Proteins
  • Pregnancy Proteins
  • Suppressor Factors, Immunologic
  • early pregnancy factor

Supplementary concepts

  • Leukodystrophy, Hypomyelinating, 4