A novel rearrangement of occludin causes brain calcification and renal dysfunction

Hum Genet. 2013 Nov;132(11):1223-34. doi: 10.1007/s00439-013-1327-y. Epub 2013 Jun 21.


Pediatric intracranial calcification may be caused by inherited or acquired factors. We describe the identification of a novel rearrangement in which a downstream pseudogene translocates into exon 9 of OCLN, resulting in band-like brain calcification and advanced chronic kidney disease in early childhood. SNP genotyping and read-depth variation from whole exome sequencing initially pointed to a mutation in the OCLN gene. The high degree of identity between OCLN and two pseudogenes required a combination of multiplex ligation-dependent probe amplification, PCR, and Sanger sequencing to identify the genomic rearrangement that was the underlying genetic cause of the disease. Mutations in exon 3, or at the 5-6 intron splice site, of OCLN have been reported to cause brain calcification and polymicrogyria with no evidence of extra-cranial phenotypes. Of the OCLN splice variants described, all make use of exon 9, while OCLN variants that use exons 3, 5, and 6 are tissue specific. The genetic rearrangement we identified in exon 9 provides a plausible explanation for the expanded clinical phenotype observed in our individuals. Furthermore, the lack of polymicrogyria associated with the rearrangement of OCLN in our patients extends the range of cranial defects that can be observed due to OCLN mutations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain / physiopathology*
  • Calcinosis / physiopathology*
  • Canada
  • Child, Preschool
  • Chromosome Mapping
  • DNA Copy Number Variations
  • Exome
  • Exons
  • Female
  • Gene Deletion
  • Gene Rearrangement*
  • Genotype
  • Homozygote
  • Humans
  • Introns
  • Kidney / physiopathology*
  • Malformations of Cortical Development / genetics
  • Multiplex Polymerase Chain Reaction
  • Mutation
  • Occludin / genetics*
  • Occludin / metabolism
  • Pedigree
  • Phenotype
  • Polymorphism, Single Nucleotide
  • RNA Splicing
  • Sequence Analysis, DNA


  • OCLN protein, human
  • Occludin