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A novel rearrangement of occludin causes brain calcification and renal dysfunction
Ist Teil von
Human genetics, 2013-11, Vol.132 (11), p.1223-1234
Ort / Verlag
Berlin/Heidelberg: Springer Berlin Heidelberg
Erscheinungsjahr
2013
Quelle
MEDLINE
Beschreibungen/Notizen
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.