Genetic mutation in cilia causes congenital disease

Oral-facial-digital (OFD) syndrome is a rare congenital disorder that causes abnormalities in the oral cavity, face and digits. It arises from defects in cilia, which disrupts signaling pathways.

A team of researchers led by Maxence Nachury of Stanford University and including André Mégarbané from Saint Joseph University in Lebanon have identified a new subtype of OFD that leads to microcephaly and cerebral malformations alongside the standard OFD symptoms, publishing their findings in Nature Genetics¹.

Previous work has linked OFD syndrome to mutations in a gene called OFD1. Now, the researchers have associated this newly identified subtype of OFD to mutations in a gene called C2CD3 and proposed a model for the underlying mechanism.

By using fluorescence microscopy, they tracked the location of the protein products of these genes and found both OFD1 and C2CD3 to colocalize at the distal end of centrioles, which are responsible for the assembly of cilia. The two proteins have opposing functions, where C2CD3 promotes centriole lengthening and OFD1 inhibits centriole elongation. When they are mutated, regulation of centriole length is lost, which leads to the formation of defected cilia that cause the developmental anomalies seen in OFD patients.

“We know that centriole length is very tightly set in each organism but to date, no mechanism has emerged that may set the length,” says Nachury. “The opposing effects of C2CD3 and OFD1 provide a possible mechanism for setting centriole length at a precise value.”

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