Recessive mutations in COL25A1 are a cause of congenital cranial dysinnervation disorder

Am J Hum Genet. 2015 Jan 8;96(1):147-52. doi: 10.1016/j.ajhg.2014.11.006. Epub 2014 Dec 11.


Abnormal ocular motility is a common clinical feature in congenital cranial dysinnervation disorder (CCDD). To date, eight genes related to neuronal development have been associated with different CCDD phenotypes. By using linkage analysis, candidate gene screening, and exome sequencing, we identified three mutations in collagen, type XXV, alpha 1 (COL25A1) in individuals with autosomal-recessive inheritance of CCDD ophthalmic phenotypes. These mutations affected either stability or levels of the protein. We further detected altered levels of sAPP (neuronal protein involved in axon guidance and synaptogenesis) and TUBB3 (encoded by TUBB3, which is mutated in CFEOM3) as a result of null mutations in COL25A1. Our data suggest that lack of COL25A1 might interfere with molecular pathways involved in oculomotor neuron development, leading to CCDD phenotypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child
  • Exome
  • Female
  • Genes, Recessive*
  • Genetic Linkage
  • Humans
  • Male
  • Mutation
  • Neurogenesis / genetics
  • Non-Fibrillar Collagens / genetics*
  • Non-Fibrillar Collagens / metabolism
  • Ocular Motility Disorders / genetics*
  • Oculomotor Nerve Diseases / genetics*
  • Phenotype
  • Tubulin / genetics
  • Tubulin / metabolism


  • COL25A1 protein, human
  • Non-Fibrillar Collagens
  • TUBB3 protein, human
  • Tubulin