A new score classifying dominant disease-causing mutations has found that just over half act via loss of function, with gain-of-function and dominant-negative mechanisms making up the rest. Researchers at the Institute of Genetics and Cancer have developed a new ‘missense loss-of-function’ (mLOF) score to measure disease-causing mutations in proteins which lead to genetic disease.Genetic diseases can be caused by many different types of changes to proteins: loss-of-function (LOF), which stops the protein from working at all; gain-of-function (GOF), which makes it overactive or gives it new abilities; and dominant-negative (DN), which disrupts the function of the normal protein in people who have one healthy copy of the gene. Correctly identifying these mechanisms matters because each may require different treatments, such as replacing a missing protein, blocking an overactive one, or silencing a faulty copy.The mLOF score uses 3D protein structures to measure how damaging and how spread out disease-causing mutations are within a protein and helps distinguish between LOF and other mechanisms.Analysing almost 2,000 disease genes and nearly 3,000 conditions, the researchers found that GOF and DN mechanisms together explain nearly half of diseases in dominant genes. Many genes with more than one disease phenotype use more than one mechanism, meaning different forms of the same disease gene may need different treatments. Our method is available as an online tool, allowing researchers and clinicians to estimate likely disease mechanisms for sets of mutations, supporting better diagnosis and personalised medicine. Mihaly Badonyi Post-Doctoral Research Fellow, MRC Human Genetics Unit Read the paper in Nature Communications Joe Marsh Research Group Photo credit: Mihaly Badonyi Tags 2025 Publication date 25 Sep, 2025
