these factors is shown to increase levels of exon skipping. The TDP-43 protein is responsible for physically silencing the exon splicing site once it is recruited by the exonic splicing silencer (TG)mT(n). TDP-43 is a DNA binding protein and repressor, it binds to the TG repeat to cause exon 9 skipping. The role of the T tracts is not well understood. Spinal muscular atrophy Spinal muscular atrophy is caused by the homozygous loss of the SMN1 gene. Humans have two isoforms of the SMN (survival motor neuron) gene, SMN1 and SMN2. The SMN1 gene produces a complete transcript, while SMN2 produces a transcript without exon 7 which results in a truncated protein. The ESS that contributes to the disease phenotype is the UAGACA nucleotide sequence. This sequence arises when a C-to-T mutation occurs at position +6 in exon 7 of the SMN2 gene. This transition point mutation leads to the exclusion of exon 7 from the mRNA transcript, it is also the only difference between the SMN2 and SMN1 gene. The UAGACA ESS is thought to work by disrupting an exonic splicing enhancer and attracting proteins that inhibit splicing by binding sequences on exon 7. Ataxia telangiecstasia Mutations in the ATM gene are responsible for Ataxia telangiecstasia. These mutations are generally single base pair substitutions, deletions, or micro-insertions. A 4-nucleotide deletion within intron 20 of the ATM gene disrupts an exonic splicing silencer and causes the inclusion of a 65-nucleotide cryptic exon in the mature transcript. The inclusion of the cryptic exon results in protein truncation and atypical splicing patterns. References Genetics