Defects in Primary Cilia Underlie Many Diseases

For many years, the existence and function of the primary cilium was ignored. However, this situation has changed dramatically over the last decade as it has become appreciated that defects in intraflagellar transport result in the loss of primary cilia in mice (Figure 18-35d), and as diseases have been traced to defects in primary cilia and IFT. One of the first clues came from the discovery that loss of a mammalian homolog of a Chlamydomonas IFT protein results in defects in the primary cilia and causes autosomal dominant polycystic kidney disease (ADPKD). It is believed that the primary cilia on the epithelial cells of the kidney collecting tubule act as mechanochemical sensors to measure the rate of fluid flow by the degree to which they are bent.

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In another example, patients with Bardet-Biedl syndrome have retinal degeneration, polydactyly (from the Greek for “many fingers”), and obesity. The syndrome can be caused by mutations in any one of 14 genes and has been traced to defects in the function of primary cilia. Many of these genes encode subunits of the BBsome, an octameric complex that forms a coat with structural elements in common with COPI, COPII, and clathrin (described in Chapter 14) and that traffics membrane proteins to cilia. While defects in many of the BBsome’s components do not affect the structure of the primary cilium itself, they result in a lack of specific membrane receptors that would normally be delivered to primary cilia through the interaction of the BBsome with the IFT apparatus. For example, the polydactyly seen in patients with Bardet-Biedl syndrome is due to a loss of localized Hedgehog signaling (see Chapter 16) in the primary cilium that is necessary for patterning during embryogenesis.