Structural basis for the dominant or recessive character of GLIALCAM mutations found in leukodystrophies

Hum Mol Genet. 2020 May 8;29(7):1107-1120. doi: 10.1093/hmg/ddaa009.


Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a type of leukodystrophy characterized by white matter edema, and it is caused mainly by recessive mutations in MLC1 and GLIALCAM genes. These variants are called MLC1 and MLC2A with both types of patients sharing the same clinical phenotype. In addition, dominant mutations in GLIALCAM have also been identified in a subtype of MLC patients with a remitting phenotype. This variant has been named MLC2B. GLIALCAM encodes for an adhesion protein containing two immunoglobulin (Ig) domains and it is needed for MLC1 targeting to astrocyte-astrocyte junctions. Most mutations identified in GLIALCAM abolish GlialCAM targeting to junctions. However, it is unclear why some mutations behave as recessive or dominant. Here, we used a combination of biochemistry methods with a new developed anti-GlialCAM nanobody, double-mutants and cysteine cross-links experiments, together with computer docking, to create a structural model of GlialCAM homo-interactions. Using this model, we suggest that dominant mutations affect different GlialCAM-GlialCAM interacting surfaces in the first Ig domain, which can occur between GlialCAM molecules present in the same cell (cis) or present in neighbouring cells (trans). Our results provide a framework that can be used to understand the molecular basis of pathogenesis of all identified GLIALCAM mutations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Astrocytes
  • Brain / metabolism*
  • Brain / pathology
  • Brain / ultrastructure
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / ultrastructure
  • Cysteine / genetics
  • Cysts / chemistry
  • Cysts / genetics*
  • Cysts / pathology
  • Edema / genetics
  • Edema / pathology
  • HeLa Cells
  • Hereditary Central Nervous System Demyelinating Diseases / genetics*
  • Hereditary Central Nervous System Demyelinating Diseases / pathology
  • Humans
  • Membrane Proteins / genetics*
  • Membrane Proteins / ultrastructure
  • Molecular Docking Simulation
  • Mutation
  • Phenotype
  • Protein Conformation*
  • Protein Multimerization
  • White Matter / metabolism
  • White Matter / pathology
  • White Matter / ultrastructure


  • Cell Cycle Proteins
  • HEPACAM protein, human
  • MLC1 protein, human
  • Membrane Proteins
  • Cysteine

Supplementary concepts

  • Megalencephalic leukoencephalopathy with subcortical cysts