WDR35

The WDR35 gene is the most commonly mutated gene in people with cranioectodermal dysplasia; at least eight mutations in this gene have been identified in affected individuals. This condition is characterized by an elongated head (dolichocephaly) with a prominent forehead and other distinctive facial features; short bones; and abnormalities of certain tissues known as ectodermal tissues, which include the teeth, hair, nails, and skin.

The WDR35 gene mutations involved in cranioectodermal dysplasia reduce the amount of functional WDR35 protein. A shortage or reduction in activity of this component of the IFT-A complex impairs the function of the entire complex, disrupting transport of proteins and materials from the tips of cilia. As a result, assembly and maintenance of cilia is impaired, which leads to a smaller number of cilia and abnormalities in their shape and structure. Although the mechanism is unclear, a loss of normal cilia impedes proper development of bone and other tissues, leading to the features of cranioectodermal dysplasia. Some researchers suggest that disrupted intraflagellar transport prevents signaling through the Sonic Hedgehog pathway, which could impact cell growth and other functions in several tissues throughout the body.

MedlinePlus Genetics provides information about Asphyxiating thoracic dystrophy

WDR35 gene mutations can cause short-rib polydactyly type 5, a severe condition with signs and symptoms similar to those of cranioectodermal dysplasia (described above); however, affected individuals do not survive to birth. Bone abnormalities in short-rib polydactyly type 5 include extremely short ribs, short arms and legs, and extra fingers or toes (polydactyly). Additional features include abnormalities in one or more organs, including the heart, kidneys, liver, and intestines. The severity of this condition is thought to be caused by a severe loss of function of the WDR35 protein, which likely disrupts the function of cilia to a greater degree than in cranioectodermal dysplasia.