DNA sequencing using the SOLiD technique identified a C to T transition at position 44906 of the genomic DNA sequence of Dnmt1 (NC_000075, sense strand).  The mutation lies in the splice acceptor site of intron 37 of the 39 exon gene, and affects a cytosine base seven nucleotides from the next exon.  The mutation has been confirmed by DNA sequencing using the Sanger method (see trace files for B5639).

DNA (cytosine-5)-methyltransferase 1 (Dnmt1) methylates CpG residues, preferentially those that exist in hemimethylated DNA (Uniprot P13864).  As such, Dnmt1 is essential for the transmission of epigenetic information from parent to offspring, and acts to maintain methylation patterns established during development.  Dnmt1 associates with DNA replication sites during S phase, and maintains the methylation pattern in the newly synthesized strand.  It associates with chromatin during G2 and M phases, and coordinates DNA and histone methylation by direct binding to HDAC2.  It has been shown to associate with Dnmt3b and regulate the activation of Bag1 gene expression by modulating dimethylation of histone H3 at lysines 4 and 9.  Mutations causing partial or severe loss of function were homozygous lethal by embryonic day 9.5, with lack of appropriate genomic imprinting observed at several loci.

Alternative splicing of three 5’ exons of Dnmt1 yields three transcripts (each specifically expressed in distinct tissues) that subsequently result in two translation products, a 1620 amino acid protein, and a 1602 amino acid protein.  Dnmt1 contains Bromo Adjacent Homology (BAH) domains I and II, a zinc finger domain, a catalytic DNA methyltransferase domain, and a nuclear localization signal.  It functions as a homodimer. 

The mutation may cause skipping of exon 38, and a frameshift thereafter.  Because the frameshift would affect the catalytic domain, it is likely that protein function would be compromised.