What is known about the protein structure and function?
 

The hMLH1 protein has 756 amino acids and has been completely sequenced.  The protein has 2 conserved regions at the amino terminus. In other words, there are two sections of the protein that are nearly identical in the proteins of other organisms.  (Ref. 2) These amino acid sequences are (with single letter abbreviations) KELVEN and GFRGEA. The hMLH1 protein is 41% identical to the yeast DNA mismatch gene yMLH1, with the last 13 amino acids being identical between the two proteins. The protein is composed of 19 exons,  50% of all MLH1 mutations that have been described occur in exons 15 and 16 (Ref. 2) The first seven exons are highly conserved between MLH1 and PMS1.

 
    Studies from 1993 suggested that individuals with HNPCC had impaired T-cell function. There was evidence of lower levels of natural killer cells. (Ref. 3) These cells are a type of white blood cell which target and kill specific invading cells. There was also evidence of a slow response of white blood cells to attack foreign invaders in culture. The hypothesis of the MLH1 gene causing immunodeficiency was abandoned when newer studies began to support the idea of the MLH1 gene and resulting protein being involved in DNA mismatch repair. The human MLH1 protein has not been thoroughly investigated yet, but many hypotheses have been drawn based on its similarity to DNA mismatch repair proteins in other organisms (Ref. 8)
 
    There are thought to be multiple proteins involved in the repair of DNA. The process of DNA mismatch repair has been thoroughly studied in E. Coli. According to this system, one protein recognizes and binds to mismatched DNA. A second protein, called Mut L (which closely resembles the hMLH1 protein), acts as an interface with a third protein. Once activated, this third protein breaks the bonds of the DNA backbone and removes the damaged region. (Ref. 8) A mutation in any of the DNA repair proteins means the organism’s DNA is more susceptible to mutations.

   One proposed explanation for the increased frequency of mutation is dinucleotide repeat instability. In areas of DNA where two nucleotides are repeated, there is an increase in spontaneous mutation within these repeats. (Ref. 2) This can lead to more than a 100 fold increase in the mutation rate (Ref. 8). Mutations resulting from dinucleotide repeat instability are common in HNPCC families. Consistent with this idea is the evidence from a study showing that the HNPCC tumor DNA had different markers than the normal tissue DNA indicating replication error. (Ref. 1)

    An issue that is still under considerable investigation is why the colon is the most frequent target for tumor development. Mismatch repair genes are housekeeping genes, meaning they are expressed in nearly every cell and are essential for normal cell function. It is not yet understood why tumor development is restricted to certain organs. One possibility is that the colon mucosal layer has more exposure for long time periods to carcinogens found in food, toxic metabolites, and bacterial products. Another possibility is that the colon mucosal layer has a high proliferation rate which could overburden and exhaust the mismatch repair genes. This might possibility would also hold true for the  endometrial mucosal layer.
 

Unlike diseases like Down Syndrome, HNPCC is not caused by a specifically recognized mutation. There are 4 genes that have been linked to HNPCC, and for each of those genes there is a multitude of mutations that can occur within the genetic code. This graph shows the extent of the heterogeneity of HNPCC. In other words, the slice of the graph is proportional to the number of different of genetic mutations that give rise to the same disease. HNPCC ranks second in hereditary colon cancers.

 

    A study completed in 1996 using mice showed that the MLH1 protein was not only involved in DNA mismatch repair, but also in meiotic crossing over. Mice that were created with a mutation in the MLH1 gene not only showed mutations that are associated with HNPCC, but resulted in sterility of both males and females. Sterility is usually associated with disruption in the normal meiotic process. They found evidence showing MLH1 located at chiasmata sites on meiotic chromosomes. Chiasmata are the cross-shaped structures seen during crossing over of chromosomes in meiosis. No other studies have been found that support this result, and sterility has not been associated with HNPCC in humans. (Ref. 2)
 
What other sources about the protein are available?

• Many of the known mutations in the genetic code can be found here.
• Several of the more common mutations and their affect on the protein can be found at the following link.