Implications of RNA‐binding Proteins for Human Diseases


RNA‐binding proteins play pivotal roles in ribonucleic acid (RNA) metabolism. The identification of mRNA targets of RNA‐binding proteins has also contributed to the delineation function of these proteins. The different tissue specificity and subcellular localisation of the RNA‐binding proteins show that these proteins can regulate specific aspects of mRNA processing and function in cells, from splicing and transport to translation and stability. Mutations, deletions and/or autoimmune reactions affecting RNA‐binding proteins lead to alterations in cellular processes, normal development and various disorders. The vast majority of these diseases are neurological or neuromuscular disorders and includes myotonic dystrophy, spinal muscular atrophy, oculopharyngeal muscular dystrophy, amyotrophic lateral sclerosis, fragile X syndrome, fragile X associated tremor/ataxia syndrome and paraneoplastic opsoclonus‐myoclonus ataxia. Altered expression of RNA‐binding proteins is also a common feature in various cancers. Understanding the molecular mechanisms of RNA‐binding proteins aberrations in disease could lead to better‐targeted therapies.

Key Concepts:

  • RNA‐binding proteins are key components in RNA metabolism.

  • RNA‐binding proteins contain modular amino acid sequences that mediate RNA binding.

  • The two largest RBP families contain the RNA recognition motif (RRM) and the K homology (KH) domains.

  • Deleterious RNA‐dominant loss‐of‐function or gain‐of‐function mechanisms are associated with defects in RBPs.

  • Several neurological and neuro‐muscular diseases are linked to defects in RBPs.

  • FXS is caused by CGG repeat in the 5′ untranslated region of the FMR1 gene.

  • Antibodies against RBPs Hu and Nova are implicated in the pathogenesis of paraneoplastic neurologic syndromes.

  • DM1 is associated with the accumulation of RNA aggregates and misregulation of the RBPs, MBNL1 and CUGBP1.

  • Translocations of genes encoding RBPs and aberrant expression RBPs have been associated with various cancers.

Keywords: RNA binding proteins; complex human diseases; RNA metabolism; neurological disorders; cancer; RNA; neuromuscular diseases

Figure 1.

Functional domains of some RBPs implicated in human diseases. Functional domains of some RNA‐binding proteins implicated in human diseases, showing variability in the RNA‐binding domains and size. These domains include the RNA‐recognition motif (RRM; by far the most common RNA‐binding protein module) and the (KH) domain (which can bind both single‐stranded RNA and DNA). Less common RNA‐binding functional modules like the tudor domain found in SMN which bind RNA and methylated histones; zinc finger motifs CCCH (Cys3His or C3H motifs) or CCCH (CysCysHisCys) found in MBNL1, TTP and Lin‐28; CSD () found in Lin‐28. Indicated key residues include R/S, Arg/Ser; P, proline; Y, tyrosine; G, glycine; A, alanine; K, lysine; and Q, glutamine. The RBPs shown include ASF/SF2, alternative splicing factor/splicing factor 2; CUGBP, CUG‐binding protein; FMRP, ; FUS/TLS, fused in sarcoma/translocated in liposarcoma; KSRP, KH type splicing regulatory protein; MBNL1, RNA‐binding proteins muscleblind‐like 1; Msi1, Musashi‐1; Nova 1 and 2, Neuro‐oncological ventral antigen 1 and 2; PABP, poly(A)‐binding protein 1; Sam68, src‐associated in mitosis, 68 kDa; SMN, survival motor neuron protein; TDP‐43, TAR (trans‐activation response) DNA and RNA‐binding protein 43; and TTP, tristetraprolin.



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Further Reading

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Van Meerbeke JP and Sumner CJ (2011) Progress and promise: the current status of spinal muscular atrophy therapeutics. Discovery medicine 12: 291–305.

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Lukong, Kiven E, and Fatimy, Rachid El(May 2012) Implications of RNA‐binding Proteins for Human Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023866]