title: Two novel CCDC88C mutations confirm the role of DAPLE in autosomal recessive congenital hydrocephalus.
abstract: BACKGROUND
  Human congenital non-syndromic hydrocephalus is a vastly heterogeneous condition. A subgroup of cases are not secondary to a specific cause (eg, a neural tube defect), and within this subgroup, autosomal recessive inheritance has been described. One homozygous mutation in the DAPLE (Dvl-associating protein with a high frequency of leucine residues) protein-encoding gene CCDC88C (coiled-coil domain containing 88C) has recently been reported in a single family. The role of this gene has not been validated in another family, and no other autosomal recessive gene has been reported.
  
  
  METHODS
  We used homozygosity mapping and whole exome sequencing in two families with primary, non-syndromic congenital hydrocephalus from two different ethnic backgrounds.
  
  
  RESULTS
  In each family, we identified a novel homozygous mutation of CCDC88C. One mutation produced a premature stop codon at position 312 of the protein, while the second mutation induced a frameshift in the last exon, producing a stop codon that truncated the extreme C-terminus of DAPLE, including the 2026-2028 Gly-Cys-Val motif known to bind the post synaptic density protein (PSD95), Drosophila disc large tumor suppressor (Dlg1), and zonula occludens-1 protein (zo-1) (PDZ) domain of Dishevelled.
  
  
  CONCLUSIONS
  Our data validate CCDC88C as causing autosomal recessive, primary non-syndromic congenital hydrocephalus, suggesting this gene may be an important cause of congenital hydrocephalus, and underscore the important role of the C-terminal PDZ domain-binding motif in the DAPLE protein.
authors.affiliation: Institute of Interdisciplinary Research – IRIBHM, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Anais
authors.initials: A
authors.lastname: Drielsma
authors.forename: Chaim
authors.initials: C
authors.lastname: Jalas
authors.forename: Nicolas
authors.initials: N
authors.lastname: Simonis
authors.forename: Julie
authors.initials: J
authors.lastname: Désir
authors.forename: Natalia
authors.initials: N
authors.lastname: Simanovsky
authors.forename: Isabelle
authors.initials: I
authors.lastname: Pirson
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
authors.forename: Marc
authors.initials: M
authors.lastname: Abramowicz
authors.forename: Simon
authors.initials: S
authors.lastname: Edvardson
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D006849:Hydrocephalus / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D054731:PDZ Domains; D010375:Pedigree; D011485:Protein Binding; D011859:Radiography; D017422:Sequence Analysis, DNA
chemical_list: C580811:CCDC88C protein, human; D018389:Codon, Nonsense; D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins