The MLH1 gene is composed of 19 exons spanning in a region of 57360 bp.

The transcribed mRNA has 2524 bp

Aminoacids: 756. Molecular Weight: 84.6 kDa. MLH1 is a protein involved in the mismatch repair process after DNA replication. It contains an ATPase domain and two interaction domains, one for MutS homologs (MSH2, MSH3, MSH6) and the other for PMS2, MLH3 or PMS1.

Nuclear

MLH1 has no known enzymatic activity. MLH1 forms a heterodimer with PMS2 known as MutLa, although it can also bind to PMS1 or MLH3. This heterodimeric complex binds to the heteroduplexes MutSa (composed of MSH2 and MSH6) or MutSb (composed of MSH2 and MSH3), which recognize DNA lesions. The heterodimer formed by MLH1 is responsible for the recruitment of the proteins needed for the excision and repair synthesis.

MLH1 is homologue to the bacterial MutL gene, specially in the N-terminal region, and MLH1 homologues are also present in eukaryotes (for example in Mus musculus, Drosophila melanogaster, Caenorhabditis elegans or Saccharomyces cerevisae)

There are over 300 MLH1 germline mutations described all along the gene that cause hereditary non-polyposis colorectal cancer (HNPCC, see below). This mutations are not present in any particular hotspot or zone of the gene and include either nucleotide substitutions (missense, nonsense or splicing errors) or insertions/deletions (gross or small). In most of these mutations the resulting protein is truncated. There are also founding mutations which account for a high proportion of the HNPCC tumours in some specific populations (for example there are two Finnish mutations that delete the exons 16 or 6). Some germline genetic changes have also been described in both exons and introns as non pathogenic.

There are described some sporadic mismatch repair deficiency cases (sporadic MSI) with somatic MLH1 mutations, although most of them have MLH1 promoter hypermetilation.