Impact of missense mutations in recessive Mendelian disease: insight from ciliopathies

More than half of the mutations that have been identified in human genetic disorders are single letter alterations that affect just one of hundreds of amino acid building blocks in a protein. They are known as missense mutations. Unlike other types of mutation which destroy protein function, it is thought that many missense mutations only partially reduce protein function. This is particularly true for an estimated 600 genetic diseases where only missense mutations are observed.

Most genes have many activities within the cell, but we propose that this category of missense mutation only affects a subset of these. We have developed complementary approaches to systematically analyse these mutations, which we will apply to 147 mutations causing one of the largest human disease categories known as ciliopathies.

Our research will help to narrow down particular mechanisms of recessive Mendelian disease.