Polymorphisms of the untranslated regions and disease
It is well known that mutations occur in the coding sequence directly Mutations affecting mRNA processing, export, stability, and translational control all have the potential to play a major role in the pathogenesis of disease states. Recent evidence is mounting however that many diseases can result from mutations that influence the many aspects of mRNA metabolism. Important regulatory elements for post-transcriptional control are encoded in the 5’ and 3’ untranslated regions (UTRs).
The 5’ UTR provides a unique opportunity for the regulation of protein synthesis since it participates in the recruitment and scanning of the 40S ribosomal subunit prior to translation initiation (Mendell., 2001).
Hyperferritinemia / cataract syndrome (HHCS) is caused by mutations in the 5’ UTR of the L-ferritin gene. Ferritin is tightly regulated by iron-responsive elements (IREs), hairpin structures in the 5’ UTR which inhibit translation under conditions of low intracellular iron through interactions with iron responsive proteins (IRPs). In HHCS, the IRE is disrupted by mutation leading to high ferritin production (Cazzola and Skoda., 2000).
The 40S ribosomal subunit normally initiates scanning from the 5’ cap, however there are examples of mammalian genes that recruit ribosomes directly to internal sites within the 5’ UTR through cis-acting elements termed internal ribosome entry sites (IRESs). A mutation in the 5’ UTR of the connexin-32 gene caused Charcot-Marie-Tooth disease by abolishing the function of the IRES (Hudder and Werner, 2000). On the other hand, a mutation in the c-myc 5’ UTR increased the activity of an IRES, causing excess c-myc production and contributing to multiple myeloma (Chappell et al., 2000).
The composition of complexes containing the RBP fragile X mental retardation protein (FMRP) were analyzed by Brown et al. A mutation FMRP causes fragile X syndrome and mental retardation. Approximately 430 mRNAs were co-precipitated with FMRP in the analysis. Greater than 50% of these mRNAs had abnormal polysomal profiles.
Although 3’ UTRs contain only approximately 0.2% of known disease-associated mutations, this is likely to represent a rather conservative estimate of their actual prevalence (Chen et al., 2006). Autosomal dominant cerebellar ataxia linked to chromosome 16q22.1 is associated with a single-nucleotide substitution in the 5' untranslated region of the gene encoding a protein with spectrin repeat and Rho guanine-nucleotide exchange-factor domains (Ishikawa et al., 2005).
Di Paola et al. recently identified a variation in 3' UTR of hPTP1B increases specific gene expression and associates with insulin resistance.
Thus, polymorphisms are also found in non-coding regions as well and can play important roles in disease pathogenesis.
