Which type of mutations are involved?
Where is other information about mutations of the MLH1 gene?

Which type of mutations are involved?

     A mutation is any detectable and heritable change in the genetic material.  In order to understand the effects of mutations, it is important to understand how DNA codes for specific amino acids.  DNA is read in triplet codons, which are units of 3 contiguous bases of DNA.  The chart below illustrates which combinations of 3 bases specify which amino acid.

    The codons on this chart are based on the mRNA copy of the DNA strand.  This strand can be mutated in many different ways to give different sequences of amino acids.  Although there are many different kinds of mutations, they all affect the same gene, MLH1.  The different types of mutations which play a role in causing HNPCC include substitutions, deletions, insertions, and frameshift mutations.  A substitution, or point mutation, is a mutation in which a single base is replaced by another.  Depending on which base is mutated, this type of mutation may or may not affect the type of amino acid produced.  For example, if an mRNA strand reads

        GCGUAUAAG, it codes for Alanine-Tyrosine-Lysine.

    A point mutation at the third position causes the strand to read

       GCCUAUAAG, but it still codes for Alanine-Tyrosine-Lysine.
 

    A point mutation in the second position, however, causes the strand to read

       GUGUAUAAG, which causes it to code for Valine-Tyrosine-Lysine.
 

    Deletions occur when a base is deleted from the coding strand.  Insertions are the result of an extra base being added to the coding strand.  Both deletions and insertions result in frameshift mutations in which the grouping of 3 contiguous bases is disrupted and the reading frame is shifted.  This is illustrated in the following examples.  If the first adenine (A) base is deleted from the original sequence, the resulting strand reads

       GCGUUAAG, and codes for Alanine- Leucine-[Serine or Argenine]
 
    This deletions causes the triplet groupings to change.  An insertion causes the same effect, only the reading frame shifts in the opposite direction.  If there is an insertion of an A before the first A in the original sequence, the new strand now reads

       GCGUAAUAAG, and codes for Alanine-Stop.
 

    The stop codon instructs the end of protein synthesis, and in these cases, the protein is truncated too early, as a result of the frameshift.  As one can see, any of these mutations have the capacity to drastically alter the resulting protein structure, and thus the protein function.  All of these types of mutations have been isolated as contributors to cases of HNPCC.  While it would be impossible to list all of the mutations which play a role in HNPCC, the following sites contain more information regarding mutations in the MLH1 gene.

Where is other information about mutations of the MLH1 gene?

• Categorization of all the known pathogenic, or disease-causing, mutations of MLH1 by exon and their effects on the gene structure, translation, and transcription can be found by following this link.
• A list of all the intragenic mutations of the MLH1 gene and their effects on the gene structure, translation, and transcription can be found at the following link.
• Eight common mutations, describes how they were found, and elucidates the consequences of the mutations can be found at the following link.
• More information about the location of the various mutations can be found at this site.