Expandable Tandem Repeat Above the Instability Threshold
trigger
The shared substrate is a germline tandem repeat expanded (or in the premutation range) above a length/instability threshold, at which the repeat forms slipped-strand and hairpin secondary structures that become substrates for aberrant repair. This applies across the repeat classes of the STR expansion diseases — CAG (Huntington disease, the polyglutamine SCAs, DRPLA, SBMA), CGG (FMR1), CTG (DMPK), and GAA (FXN) — with the specific expandable locus substituted by the conforming disorder.
Downstream
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Aberrant Mismatch-Repair Processing of the Repeat
The slipped/hairpin repeat structure formed above the instability threshold is engaged by the MMR machinery.
Aberrant Mismatch-Repair Processing of the Repeat
amplifier
The MutSβ complex (MSH2-MSH3) recognizes the slipped/hairpin repeat structure and, instead of faithfully repairing it, licenses incremental expansion; the MutLγ complex (MLH1-MLH3) acts downstream of MutSβ to effect the expansion, while FAN1 (an interstrand-cross-link-repair nuclease) and EXO1 oppose it and are protective. This aberrant, gain-of-toxic-outcome use of a normally protective repair pathway is the disorder-agnostic molecular driver of the expansion; human genetic-modifier studies converge on these same MMR factors.
Downstream
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Somatic Repeat Expansion in Post-Mitotic Cells
Aberrant MMR processing drives repeated rounds of incremental expansion in somatic tissue.
Somatic Repeat Expansion in Post-Mitotic Cells
central effector
Because the aberrant MMR-driven expansion continues throughout life and is not limited to replication, the repeat keeps expanding in specific post-mitotic somatic cells — most consequentially neurons — generating a mosaic of progressively larger alleles far exceeding the inherited germline length. This ongoing, cell-type-biased somatic expansion (not the static germline allele) is the rate-limiting driver of pathology and is the key conformance target: conforming disorder entries substitute their own expanding repeat and vulnerable cell population (striatal medium spiny neurons in Huntington disease; cerebellar and brainstem neurons in SCA3).
Downstream
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Cell-Type-Selective Toxicity Threshold Crossing
When somatic expansion in a vulnerable cell exceeds its toxicity threshold, the cell tips into the disease-specific downstream consequence.
Cell-Type-Selective Toxicity Threshold Crossing
effector
When cumulative somatic expansion in a vulnerable cell pushes the repeat past that cell's toxicity threshold, the cell tips into the disorder-specific downstream consequence — translated polyglutamine proteotoxicity for CAG, repeat-RNA gain-of-toxicity for CTG, or transcriptional silencing for CGG and GAA. Because the expansion rate is cell-type-specific, this threshold crossing is the event that explains the selective regional vulnerability of a ubiquitously expressed gene and is the seam handing off to the disorder's toxicity module.
Downstream
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Repeat-Length-Dependent Onset, Progression, and Anticipation
The aggregate of cell-level threshold crossings determines the organism-level timing and severity of disease.
Repeat-Length-Dependent Onset, Progression, and Anticipation
consequence
The organism-scale readout of the molecular engine: somatic-expansion burden sets the age of onset — earlier than the inherited germline allele alone predicts — and the rate of progression, while germline instability with parent-of-origin bias produces intergenerational anticipation. These are the defining clinical hallmarks of the repeat expansion diseases (mirrored by the STRchive locus tags somatic_instability, anticipation, and length_affects_onset), here derived mechanistically from MMR-driven instability rather than merely correlated with germline repeat length.