Saturday, February 20, 2016

Rare Spliceosome Diseases

In animals, DNA sequences are not transcribed directly into full-length RNA molecules, ready for translation into a final protein. There is a pre-translational process wherein transcribed sections of DNA, so-called introns, are spliced together, and a single gene can be assembled into alternative spliced products. Alternative splicing is one method whereby more than one protein form can be produced by a single gene (1). Cellular proteins that coordinate the splicing process are referred to, in aggregate, as the spliceosome. Errors in normal splicing can produce inherited disease, and it estimated that 15% of disease-causing mutations involve splicing (2), (3). Examples of spliceosome diseases are spinal muscular atrophy and some forms of retinitis pigmentosa (1). In both diseases, pathology is limited to a specific type of cell; retinal cells and their pigment layer in retinitis pigmentosa, and motor neuron cells in the spinal muscular atrophy. One might expect that mutations in spliceosomes would cause deficiencies in diverse cell types, with multi-organ and multi-system disease (e.g., syndromic disease). That this is not the case is somewhat of a mystery, and the catalyst for much speculation. Faustino and Cooper have categorized splicing diseases into different types, including: those that affect a single gene, those that affect multiple genes, those that cause aberrant splicing that result in unnatural mRNAs, and those that cause the inappropriate expression of natural mRNAs (1).

Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.

- Jules Berman (copyrighted material)

key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, DNA splicing, common diseases, jules j berman


[1] Faustino NA, Cooper TA. Pre-mRNA splicing and human disease. Genes and Dev 17:419-437, 2003.

[2] Pagani F, Baralle FE. Genomic variants in exons and introns: identifying the splicing spoilers. Nat Rev Genet 5:389-396, 2004.

[3] Fraser HB, Xie X. Common polymorphic transcript variation in human disease. Genome Res 2009 Apr;19(4):567-575, 2009.