Mutation Type And Disease Severity

However, for many genes, such as the MYOC glaucoma gene, we cannot make simple generalizations. Although many different MYOC missense mutations cause a very severe autosomal dominant form of glaucoma in children or young adults, some other missense mutations in MYOC do not cause glaucoma at all, even though they also change the amino acid and in some cases are located in regions where other missense mutations have been found to cause disease. A nonsense mutation at codon 368 in one copy of the MYOC glaucoma gene causes disease that is milder and starts later than the disease caused by many of the missense mutations, and another nonsense mutation at codon 46 was found in someone older who does not have glaucoma at all.

We also have trouble predicting what will happen when someone is homozygous for a dominant mutation. For one MYOC missense mutation that causes disease in heterozygotes, homozygosity for the disease allele results in a normal phenotype! With a different missense mutation, homozygosity causes disease that is even more severe than what we see in the heterozygotes.

Thus for some genes, such as the DMD gene, we seem to be able to generalize from the mutation type to the phenotype. Absence of gene product results in the severe phenotype; reduced function due to missense mutation in DMD results in a later-onset, more mild phenotype. However, for MYOC, we clearly cannot make simple predictions about phenotype based on mutation type. These complications mean that every new MYOC mutation that comes along requires additional analysis to determine whether it is causing disease or not. That analysis may include screening populations to find out whether that particular mutation is present in many unaffected people or looking at co-segregation in a family to find out whether the presence of the mutation correlates with the presence of the disease. Once they are developed, biochemical assays to determine whether the gene product still carries out its normal function would greatly assist in interpreting the implications of a new missense mutation.

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