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Leaky scanning occurs when ribosomes fail to recognize the first AUG start codon and instead initiate protein synthesis from a downstream start codon. This phenomenon allows cells to produce multiple protein types from a single mRNA molecule. The Kozak sequence context surrounding each AUG determines whether ribosomes will initiate translation at that position or continue scanning.

The Kozak sequence determines ribosome recognition of start codons. An optimal sequence contains a purine (adenine or guanine) at the -3 position and guanine at the +4 position relative to the AUG start codon. When optimal, nearly all ribosomes initiate at that codon. If either position lacks the required nucleotide, the sequence is weak, and many ribosomes skip it to find a stronger downstream start codon.

Ribosomes skip the first AUG when it lacks an optimal Kozak recognition sequence—specifically when a purine is absent at -3 or guanine is absent at +4. Additionally, if the first start codon is less than 12 nucleotides from the 5' end or closely spaced to another AUG, leaky scanning increases. In the peanut clump virus, approximately 30% of ribosomes bypass the weak first start codon to initiate at a downstream site.

When both start codons are in the same reading frame, leaky scanning produces protein isoforms differing only in their N-termini. The mammalian glucocorticoid receptor gene exemplifies this: two isoforms are generated—the larger 94 kDa GR1 and smaller 91 kDa GR2. Despite being smaller, GR2 is twice as efficient at gene transactivation, demonstrating that shorter isoforms can have enhanced biological activity.

When the first and downstream start codons occupy different reading frames, leaky scanning generates entirely distinct proteins with unrelated sequences and functions. The influenza A virus segment 2 mRNA demonstrates this: one protein functions as a core polymerase component essential for replication, while the other promotes apoptosis and is not required for viral replication, showing how a single mRNA encodes functionally independent proteins.

Nucleotide spacing influences leaky scanning efficiency. If the first start codon is positioned less than 12 nucleotides from the 5' end of the transcript, ribosomes may skip it. Close spacing between multiple AUG codons also promotes leaky scanning. In influenza virus B segment 6, two start codons separated by only 4 nucleotides demonstrate how proximity triggers ribosome scanning past the first codon.

Leaky scanning allows ribosomes to initiate translation at downstream start codons, producing proteins lacking N-terminal organelle-specific signal sequences. When both codons share the same reading frame, the shorter protein generated from the downstream start codon retains the same amino acid sequence but without the targeting signal. This mechanism enables cells to generate functional cytoplasmic versions of proteins that would otherwise be directed to organelles.