FST (follistatin; HGNC:3971, NCBI Gene ID 10468) is a human locus mapped to chromosome band 5q11.2 that encodes secreted autocrine/endocrine glycoprotein isoforms FST288 (tissue-bound) & FST315 (circulating). FST acts in extracellular bioneutralization of Myostatin (MSTN), Activin A (INHBA) & GDF11, together with MSTN (Myostatin Gene), INHBA (Activin A Subunit Beta-A Gene), and ACVR2B (Activin Receptor Type-2B Gene). Encodes follistatin, the extracellular glycoprotein that wraps around and neutralizes myostatin and activin A to promote muscle growth.
Genomic Organization & Cytogenetic Locus: 6-exon gene on chromosome 5q11.2 that undergoes alternative pre-mRNA splicing at exon 6 to produce two primary precursor transcripts: FST317 (yielding mature 288-residue FST288, which binds cell-surface heparan sulfate proteoglycans with high affinity) and FST344 (yielding mature 315-residue FST315, whose C-terminal acidic tail masks the heparin-binding site inside circulation).
Cellular & Tissue Expression Profile: Synthesized in ovarian granulosa cells, anterior pituitary gonadotropes and folliculostellate cells, hepatic hepatocytes (induced during exercise by high glucagon-to-insulin ratio), and regenerating skeletal muscle satellite cells.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Two follistatin molecules wrap head-to-tail around a single homodimer of Activin A (INHBA), Myostatin (MSTN), or GDF11 using their N-terminal domain and three tandem cysteine-rich follistatin domains (FSD1–FSD3), completely burying the type I and type II (ACVR2A/ACVR2B) receptor-binding interfaces with picomolar affinity and routing the ligand complex to lysosomal degradation.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Overexpression of FST in skeletal muscle produces even greater myofiber hypertrophy than MSTN knockout alone because follistatin simultaneously blocks both Myostatin and Activin A signaling through ACVR2B/ACVR2A, whereas biallelic FST loss-of-function is perinatally lethal due to musculoskeletal and diaphragmatic insufficiency.
Therapeutic & Clinical Pharmacology: The circulating non-heparin-binding isoform FST344 (which yields FST315 and avoids pituitary gonadotrope FSH suppression) has been evaluated in human clinical trials via intramuscular AAV1.CMV.FS344 gene therapy for Becker muscular dystrophy and inclusion body myositis, as well as recombinant FST-Fc fusion biologics.