frameshift mutation

**Definition:** Insertion or deletion (indel) of nucleotides in a number not a multiple of 3 (±1, ±2, ±4, etc.). Because the genetic code is read in triplets (codons), every codon downstream of the mutation is changed.

**Pathophysiology:** - The ribosome reads mRNA in a fixed reading frame set by the start codon (AUG). An indel shifts this frame. - All downstream codons are misread, giving a garbled amino acid sequence. - A premature stop codon (UAA, UAG, UGA) usually appears soon after, producing a truncated protein. - Truncated transcripts with premature stop codons are often degraded by nonsense-mediated mRNA decay (NMD), which causes loss of function. - In-frame indels (multiples of 3) add or remove whole amino acids and are usually less severe. An example is the ΔF508 deletion in CFTR, which removes 3 nucleotides (one phenylalanine).

**Severity comparison (generally, most to least severe):** Nonsense and frameshift (especially early in the gene) > missense > silent. Frameshifts near the 5' end of a gene are the most damaging. Those near the 3' end may leave a partly functional protein.

**Causes:** - Slippage of DNA polymerase in repetitive sequences (microsatellites), as in mismatch repair deficiency (Lynch syndrome, HNPCC), which causes microsatellite instability. - Error-prone repair, such as nonhomologous end joining. - Intercalating agents (e.g., ethidium bromide, acridine dyes) can cause insertions or deletions.

**High-yield clinical associations:** - **Duchenne muscular dystrophy:** Frameshift or nonsense deletions in the dystrophin gene (X-linked recessive) cause absent dystrophin and a severe phenotype. In **Becker muscular dystrophy**, in-frame deletions leave a partially functional, truncated dystrophin and a milder phenotype. This "frameshift vs. in-frame" contrast is the classic board question. - **Tay-Sachs disease:** The most common mutation is a 4-base insertion (TATC) in the HEXA gene, causing hexosaminidase A deficiency. - **CFTR (cystic fibrosis):** Many mutations, but ΔF508 is the most common and is in-frame. Do not confuse it with a frameshift. - **BRCA1/BRCA2:** Many pathogenic variants are frameshifts (e.g., BRCA1 185delAG, common in Ashkenazi Jews), causing loss of function. - **Lynch syndrome:** Mismatch repair defects cause frameshifts in microsatellite repeats of tumor suppressor genes. - **Familial hypercholesterolemia, APC (FAP), and others** also commonly have truncating frameshift variants. - **CCR5-Δ32:** A 32-bp deletion (not a multiple of 3) causes a frameshift and confers HIV resistance.

**Therapeutic angle:** - Exon-skipping antisense oligonucleotides (e.g., eteplirsen, golodirsen) restore the reading frame in Duchenne by skipping specific exons. This converts a frameshift into an in-frame (Becker-like) deletion.

**Exam pearls:** - The key check is whether the indel length is divisible by 3. If it isn't, it is a frameshift. - Frameshift is a type of mutation at the DNA level. Its consequence is loss of function, typically through premature termination. - Point mutations (substitutions) cannot cause frameshifts. Only indels do. An exception is a mutation that alters a splice site, which can cause exon skipping or intron retention and result in a frameshift.