Two novel CCDC88C mutations confirm the role of DAPLE in autosomal recessive congenital hydrocephalus

Abstract

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.

An update on research priorities in hydrocephalus: overview of the third National Institutes of Health-sponsored symposium “Opportunities for Hydrocephalus Research: Pathways to Better Outcomes”

“…Early pattern formation genes such as SHH, ZIC2, PAX6, and WNT1, neuronal path-finding genes such as L1CAM, genes related to cortical development such as POMT1, and those related to growth regulation such as PIK3CA and AKT3 have been implicated. 1,3,7,10,29,52,53,72,84,85,91,103,122 Developmental disorders presenting with hydrocephalus include neural tube disorders, forebrain and hindbrain developmental disorders, brain growth disorders, and cortical malformations. Alterations in the choroid plexus, ependyma, aqueduct, ventricles, and extraaxial spaces can also lead to hydrocephalus.…”

A novel missense mutation inCCDC88Cactivates the JNK pathway and causes a dominant form of spinocerebellar ataxia

“…Only three heterozygous candidate variants remained after this filtering step (see online supplementary tables S3 and S4). We next assessed the gene expression profile of the candidates using NCBI UniGene build 236 (UniGene)16 EST profile and found that the coiled-coil domain containing 88C ( CCDC88C ) gene,17 18 also known as D vl-associating protein with a high frequency of leucine residues ( DAPLE ),19 is the only candidate that expresses in brain (see online supplementary table S4). Gene expression data from Allen Brain Atlas20 and Human Brain Transcriptome Project21 also showed that CCDC88C has the highest average expression level in cerebellum (see online supplementary table S4).…”

Bi‐allelic mutations of CCDC88C are a rare cause of severe congenital hydrocephalus

“…Recessive mutations of CCDC88C have been identified in only four multiplex families to date, three of whom were from in-bred populations (two consanguineous families of Palestinian and Algerian origin) and one Ashkenazi Jewish family (Drielsma et al, 2012; Ekici et al, 2010) (Supplementary Table S5). Altogether, affected children had congenital hydrocephalus, seizures, and varying degrees of intellectual and/or motor delays, but no other major organ-system involvement.…”

“…Hydrocephalus was diagnosed in utero or at birth in all mutation-positive individuals, including the siblings in our report. In two previously published families, a total of six pregnancies were terminated due to prenatal findings of severe ventriculomegaly (Drielsma et al, 2012; Ekici et al, 2010). All patients underwent VP shunting within the first few weeks of life (mean age at shunt placement 5.8 days, range 5–21 days of age).…”

“…However, there continue to be significant gaps in our knowledge of these genetic causes due to absence of systematic data, and the paucity of known genes associated with isolated hydrocephalus (i.e., excluding well-studied syndromes in which hydrocephalus is a feature, such as the dystroglycanopathies). In 2010, recessive mutations of the CCDC88C gene were first identified in a large consanguineous multiplex family, with only two additional families identified since (Drielsma et al, 2012; Ekici et al, 2010; Tsoi et al, 2014). Here, we report a family of two affected children with congenital hydrocephalus due to a novel homozygous mutation in the CCDC88C gene, and we further characterize the spectrum of CCDC88C -associated hydrocephalus.…”