Family Frizzled Smoothened GPCRs

Frizzled-4 Mutations in the gene FZD4 cause familial exudative vitreoreti-nopathy (FEVR). FEVR is an autosomal dominant hereditary ocular disorder characterized by impaired development of retinal vessels and various secondary complications, including retinal folds and retinal detachments. The gene product of FZD4, frizzled-4, is a GPCR that binds the Wnt family of signaling peptides. To date, 12 mutations have been described (five deletions, one nonsense, and six missense) [227-231]. Only one frameshift mutation, L501 fs X533 that results in deletion of the receptor's carboxy-terminal tail, has been characterized in vitro [232]. This truncated receptor is retained in the ER and exerts a dominant-negative effect on wild--ype frizzled -4, preventing its ability to signal [233]. Whether this mutant form could be rescued by a pharmacological chaperone approach remains to be investigated.

The above examples provide evidence that loss-of-function mutations linked to human diseases can be found in many GPCRs and across multiple GPCR subclasses. There is little doubt that this list will continue to grow in the coming years. Additional studies will be needed to determine which of these mutations lead to GPCRs with decreased stability, misfolding, and intracellular retention that would be amenable to pharmacological chaperone therapy.

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