Mutation in Protein-Coding Gene Ccdc39 Reveals Possible Root Cause of Neonatal Hydrocephalus

Published January 9, 2018 | Development

Pediatric hydrocephalus is a life-threatening condition that affects one to three children for every 1,000 live births, and represents about a third of all congenital malformations of the central nervous system.

Although hydrocephalus results from the excess accumulation of cerebrospinal fluid (CSF) in the cerebral ventricles, the basic molecular and cellular mechanisms tregulating CSF flow in the neonatal human brain are not well characterized.

Until now, finding a mouse model that mimics human neonatal hydrocephalus has been elusive.

Research led by scientists in the divisions of Neurosurgery, Human Genetics, and Developmental Biology sheds light on how early postnatal hydrocephalus develops in a progressive hydrocephalus (PRH) mouse mutant.

Using whole-genome sequencing analysis, the team found that a homozygous splice site mutation in the gene Ccdc39 was responsible for disrupting the generation of motile cilia.

“These mutants show very robust and complete penetrance of hydrocephalus, so that was a great model to start with,” says senior author June Goto, PhD. “We still need to fully understand the mechanisms that lead to the accumulation of CSF in the cerebral ventricles. Thus, there are still a lot interesting pieces of information missing.”

The work so far reveals that Ccdc39 mutant ependymal cells develop abnormal, non-functional cilia. As a result, CSF flow becomes disorganized and ultimately stops.

“This was the first evidence implicating Ccdc39 in the development of hydrocephalus,” Goto says. “Ccdc39 was not expressed in the ependymal cells of our mutant during a critical time of brain development.”

Further study could lead to ways to modulate motile cilia and CSF flow, Goto says, which suggests an opportunity for a pharmacological intervention rather than surgery for certain forms of hydrocephalus.