Disturbed Wnt Signalling due to a Mutation in CCDC88C Causes an Autosomal Recessive Non-Syndromic Hydrocephalus with Medial Diverticulum

Abstract

The etiology of non-syndromic hydrocephalus is poorly understood. Via positional cloning in a consanguineous family with autosomal recessive hydrocephalus we have now identified a homozygous splice site mutation in the CCDC88C gene as a novel cause of a complex hydrocephalic brain malformation. The only living patient showed normal psychomotor development at the age of 3 years and 3 months and her deceased aunt, who was assumed to suffer from the same condition, had mild mental retardation. The mutation in the affected patients, a homozygous substitution in the donor splice site of intron 29, resulted in a shorter transcript due to exclusion of exon 29 and loss of functional protein, as shown by Western blotting (p.S1591HfsX7). In normal human tissue panels, we found CCDC88C ubiquitously expressed, but most prominently in the fetal brain, especially in pons and cerebellum, while expression in the adult brain appeared to be restricted to cortex and medulla oblongata. CCDC88C encodes DAPLE (HkRP2), a Hook-related protein with a binding domain for the central Wnt signalling pathway protein Dishevelled. Targeted quantitative RT-PCR and expression profiling of 84 genes from the Wnt signalling pathway in peripheral blood from the index patient and her healthy mother revealed increased mRNA levels of CCDC88C indicating transcriptional upregulation. Due to loss of CCDC88C function β-catenin (CTNNB1) and the downstream target LEF1 showed increased mRNA levels in the patient, but many genes from the Wnt pathway and transcriptional target genes showed reduced expression, which might be explained by a complex negative feedback loop. We have thus identified a further essential component of the Wnt signalling pathway in human brain development.

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

“…Recently, one homozygous mutation of CCDC88C was associated with this disorder in one consanguineous family 6. Here we report two novel homozygous mutations of CCDC88C in two independently ascertained families with multiplex cases, providing genetic validation of CCDC88C as a cause of non-syndromic hydrocephalus in humans.…”

“…Within this region, there were 60 protein-encoding genes, and CCDC88C appeared as an obvious candidate 6. Sequencing of the 30 coding exons of CCDC88C and their flanking intronic sequences revealed a single homozygous mutation, c.934C>T (p.R312X).…”

“…Using targeted quantitative RT-PCR and expression profiling of Wnt signalling genes, Ekici et al 6 described specific alterations of mRNA levels in the patient but not in his healthy mother: upregulation of β-catenin (even though β-catenin is also moderately upregulated in the mother) and of its downstream target Lef1 and reduced expression of GSK3 and Frat mRNAs.…”

“…Recently, a first autosomal recessive cause of non-syndromic congenital hydrocephalus was described by Ekici et al 6 in a family where two female patients had non-syndromic hydrocephali, associated with a splice site mutation of the CCDC88C (coiled-coil domain containing 88C) gene resulting in a premature stop codon (p.S1591HfsX7). The patients had ventricular dilatation with an interhemispheric cyst, a small vermis and an enlarged posterior fossa.…”

Profil Klinis dan Faktor Risiko Hidrosefalus Komunikans dan Non Komunikans pada Anak di RSUD dr. Soetomo

“…11 Penderita hidrosefalus terbanyak berada pada kategori infant, yaitu pasien dengan usia terbanyak antara 1-5 bulan. Studi populasi oleh Islam dkk 9 pada bayi baru lahir hingga berumur 12 bulan menunjukkan bahwa umur 4-6 bulan merupakan umur terjadinya hidrosefalus paling banyak.…”