L1 syndrome diagnosis complemented with functional analysis of L1CAM variants located to the two N-terminal Ig-like domains

Clin Genet. 2017 Jan;91(1):115-120. doi: 10.1111/cge.12763. Epub 2016 Mar 15.


L1CAM gene mutations cause neurodevelopmental disorders collectively termed L1 syndrome. Insufficient information about L1CAM variants complicates clinical prognosis, genetic diagnosis and genetic counseling. We combined clinical data, in silico effect predictions and functional analysis of four L1CAM variants, p.I37N, p.T38M, p.M172I and p.D202Y, located to the two N-terminal Ig-like domains present in five families with symptoms of L1 syndrome. Software tools predicted destabilizing effects of p.I37N and p.D202Y but results for p.T38M and p.M172I were inconsistent. Cell surface expression of mutant proteins L1-T38M, L1-M172I and L1-D202Y was normal. Conversely, L1-I37N accumulated in the endoplasmic reticulum (ER) and showed temperature-sensitive protein maturation suggesting that p.I37N induces protein misfolding. L1CAM-mediated cell-cell aggregation was severely impaired by L1CAM variants p.I37N, p.M172I and p.D202Y but was preserved by the variant p.T38M. Our experimental data indicate that protein misfolding and accumulation in the ER affect function of the L1CAM variant p.I37N whereas the variants p.M172I and p.D202Y impair homophilic interaction at the cell surface.

Keywords: L1 cell adhesion molecule; brain development; genetic counseling; neurodevelopmental disorder; protein folding; protein trafficking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites / genetics
  • Cell Communication / genetics
  • Cell Membrane / metabolism
  • Endoplasmic Reticulum / metabolism
  • Family Health
  • Female
  • Genetic Diseases, X-Linked / diagnosis
  • Genetic Diseases, X-Linked / genetics*
  • Genetic Diseases, X-Linked / metabolism
  • Genetic Predisposition to Disease / genetics*
  • HEK293 Cells
  • Humans
  • Immunoblotting
  • Immunoglobulin Domains / genetics
  • Intellectual Disability / diagnosis
  • Intellectual Disability / genetics*
  • Intellectual Disability / metabolism
  • Male
  • Microscopy, Confocal
  • Mutation, Missense*
  • Neural Cell Adhesion Molecule L1 / genetics*
  • Neural Cell Adhesion Molecule L1 / metabolism
  • Pedigree
  • Sequence Homology, Amino Acid
  • Spastic Paraplegia, Hereditary / diagnosis
  • Spastic Paraplegia, Hereditary / genetics*
  • Spastic Paraplegia, Hereditary / metabolism


  • Neural Cell Adhesion Molecule L1

Supplementary concepts

  • MASA (Mental Retardation, Aphasia, Shuffling Gait, Adducted Thumbs) Syndrome