De novo stop-loss variants in CLDN11 cause hypomyelinating leukodystrophy

Brain. 2021 Mar 3;144(2):411-419. doi: 10.1093/brain/awaa410.


Claudin-11, a tight junction protein, is indispensable in the formation of the radial component of myelin. Here, we report de novo stop-loss variants in the gene encoding claudin-11, CLDN11, in three unrelated individuals presenting with an early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia. Brain MRI showed a myelin deficit with a discrepancy between T1-weighted and T2-weighted images and some progress in myelination especially involving the central and peripheral white matter. Exome sequencing identified heterozygous stop-loss variants c.622T>C, p.(*208Glnext*39) in two individuals and c.622T>G, p.(*208Gluext*39) in one individual, all occurring de novo. At the RNA level, the variant c.622T>C did not lead to a loss of expression in fibroblasts, indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein. Extended claudin-11 is predicted to form an alpha helix not incorporated into the cytoplasmic membrane, possibly perturbing its interaction with intracellular proteins. Our observations suggest that stop-loss variants in CLDN11 expand the genetically heterogeneous spectrum of hypomyelinating leukodystrophies.

Keywords: CLDN11; exome; hypomyelinating leukodystrophy; stop-loss; tight junction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Anodontia / genetics*
  • Anodontia / pathology*
  • Ataxia / genetics*
  • Ataxia / pathology*
  • Brain / diagnostic imaging
  • Brain / pathology*
  • Child
  • Claudins / genetics*
  • Codon, Terminator / genetics
  • Female
  • Genetic Variation
  • Humans
  • Hypogonadism / genetics*
  • Hypogonadism / pathology*
  • Leukoencephalopathies / genetics*
  • Leukoencephalopathies / pathology*
  • Magnetic Resonance Imaging
  • Male
  • Pedigree


  • CLDN11 protein, human
  • Claudins
  • Codon, Terminator

Supplementary concepts

  • Leukodystrophy, Hypomyelinating, with Hypodontia and Hypogonadotropic Hypogonadism