Non-coding RNA

Most of the transcribed human genome does not encode protein. Non-coding RNAs (ncRNAs) regulate gene expression, chromatin structure, and translation. Several are relevant to clinical genetics, from XIST in X-inactivation to miRNAs used as biomarkers.

• miRNA (microRNA): 21–23 nucleotides. Pair imperfectly with the 3' UTR of target mRNAs to repress translation or trigger degradation. Processed from precursor pri-miRNA → pre-miRNA (Drosha) → mature miRNA (Dicer).
• siRNA (small interfering RNA): similar size, near-perfect complementarity, guides cleavage via the RISC complex. Used therapeutically (patisiran for hereditary ATTR amyloidosis).
• lncRNA (long non-coding RNA): longer than 200 nucleotides. Diverse roles: X-inactivation (XIST), imprinting (H19, KCNQ1OT1), tumor suppression (MEG3), oncogenic drivers.
• snRNA (small nuclear RNA): components of the spliceosome (U1, U2, U4, U5, U6).
• snoRNA (small nucleolar RNA): guide rRNA modification; deletions of SNORD116 cluster cause Prader-Willi-like phenotype.
• piRNA (Piwi-interacting RNA): silence transposable elements in the germline.
• rRNA and tRNA: structural and adaptor RNAs; mutations in some cause ribosomopathies and mitochondrial diseases.

1. RNA Pol II transcribes the pri-miRNA (primary transcript with hairpin).
2. Drosha (nuclear) cleaves pri-miRNA to pre-miRNA (about 70 nt hairpin).
3. Exported to cytoplasm; Dicer cleaves to mature double-stranded miRNA.
4. One strand (the guide) loads into RISC (RNA-induced silencing complex).
5. RISC-miRNA pairs with complementary mRNA → translational repression or mRNA cleavage.

One miRNA typically targets dozens to hundreds of mRNAs; one mRNA can be regulated by many miRNAs. Creates extensive regulatory networks.

• XIST (lncRNA) coats the inactive X in cis to establish X-inactivation.
• H19 / IGF2 / KCNQ1OT1 (lncRNAs) at 11p15 regulate imprinting in Beckwith-Wiedemann and Silver-Russell syndromes.
• Prader-Willi syndrome: minimal deletion region includes the SNORD116 snoRNA cluster; microdeletions restricted to SNORD116 can cause a PWS-like phenotype.
• RNA interference therapeutics: siRNA drugs (patisiran, inclisiran, givosiran) target hepatic transcripts. Antisense oligonucleotides (nusinersen for SMA, eteplirsen for DMD exon 51 skipping) modulate splicing.
• miRNA biomarkers: circulating miRNAs are studied as diagnostic and prognostic biomarkers in cancer and cardiovascular disease.
• DICER1 syndrome: germline DICER1 loss-of-function causes pleuropulmonary blastoma, ovarian Sertoli-Leydig tumors, thyroid tumors, and others, showing the importance of miRNA biogenesis.