Translation

Translation is the synthesis of protein from an mRNA template, performed by ribosomes in the cytoplasm (or at the rough endoplasmic reticulum for secreted/membrane proteins). The genetic code is read in codons of three nucleotides. Translation errors (premature termination, frameshift, missense) underlie many genetic diseases.

• 64 codons encode 20 amino acids + 3 stop codons (UAA, UAG, UGA: "you are away," "you are gone," "you go away").
• Degenerate: most amino acids have multiple codons; the third position is often "wobble."
• Universal: the same code in humans, bacteria, and plants (with minor exceptions in mitochondria).
• Start codon: AUG (methionine), always initiates translation.

1. Initiation: the small ribosomal subunit binds the 5' cap, scans to the Kozak sequence surrounding AUG, and recruits the initiator tRNA-Met. The large subunit joins to form the 80S ribosome.
2. Elongation: tRNAs deliver amino acids to the A site; peptide bonds form; the ribosome translocates one codon at a time.
3. Termination: stop codon enters the A site; release factors trigger polypeptide release and ribosome dissociation.

• Signal peptide cleavage: for secreted/membrane proteins.
• Folding: chaperones (Hsp70, Hsp90) guide proper conformation; misfolding drives prion and amyloid diseases.
• Glycosylation, phosphorylation, ubiquitination, lipidation: regulate activity, localization, and turnover.
• Proteolytic cleavage: many hormones (insulin) and enzymes are activated by cleaving a precursor.

• Nonsense (stop-gain) mutations: create a premature termination codon (PTC). Typically trigger nonsense-mediated decay (NMD), eliminating the mRNA before translation. If the PTC is in the last exon, NMD is evaded and a truncated protein is produced.
• Frameshift mutations: small insertions or deletions shift the reading frame, usually creating a PTC shortly downstream (most cystic fibrosis ΔF508 excepted; that's an in-frame 3-bp deletion).
• Missense mutations: one amino acid substituted for another. Effect depends on the change (conservative vs nonconservative) and the position (catalytic site vs surface loop).
• Stop-loss ("readthrough") mutations: the stop codon is mutated and translation continues into the 3' UTR. Rare but reported in hemoglobinopathies (Hb Constant Spring).

• Surveillance mechanism that degrades mRNAs containing a PTC more than about 50 nucleotides upstream of the last exon-exon junction.
• Explains why most truncating variants cause haploinsufficiency rather than a dominant-negative phenotype.
• NMD-escaping variants (last-exon PTCs, start-proximal PTCs) can produce stable truncated proteins and cause dominant-negative disease.

• Aminoglycoside readthrough therapy: some drugs (gentamicin, ataluren) promote readthrough of premature stop codons, restoring partial protein function in conditions like Duchenne muscular dystrophy (DMD stop-gain) and cystic fibrosis (class I CFTR variants).
• Mitochondrial translation: uses 22 tRNAs; mutations (MELAS tRNA-Leu m.3243A>G) cause syndromic mitochondrial disease.
• Ribosomopathies: mutations in ribosomal proteins cause Diamond-Blackfan anemia (RPS19), Shwachman-Diamond syndrome (SBDS), and dyskeratosis congenita.