IGF2 (insulin like growth factor 2; HGNC:5466, NCBI Gene ID 3481) is a human locus mapped to chromosome band 11p15.5 that encodes mature single-chain peptide hormone IGF-2 (67 aa; 7.5 kDa). IGF2 acts in paternally expressed H19/IGF2 ICR1 imprinting locus driving placental & embryonic organogenesis via IGF1R & INSR-A, together with IGF1 (Insulin-Like Growth Factor 1 Gene), IGF1R (IGF-1 Receptor Gene), and INS (Adjacent Insulin Gene at 11p15.5). Encodes paternally expressed insulin-like growth factor 2, the primary mitogenic driver of placental and embryonic growth.
Paternally expressed H19/IGF2 ICR1 imprinting locus driving placental & embryonic organogenesis via IGF1R & INSR-A
Clinical / Therapeutic Role
Paternal loss causes Silver-Russell dwarfism; loss of imprinting (biallelic expression) causes Beckwith-Wiedemann overgrowth & Wilms tumor
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 10-exon gene located at chromosome 11p15.5 immediately downstream of INS (insulin) and 100 kb upstream of the non-coding H19 lncRNA, governed by the differentially methylated Imprinting Control Region 1 (ICR1): on the maternal chromosome unmethylated ICR1 binds CTCF insulator proteins that direct downstream enhancers to H19 while silencing IGF2, whereas on the paternal chromosome methylated ICR1 blocks CTCF and allows enhancers to drive paternal IGF2 transcription across four developmental promoters (P1–P4).
Cellular & Tissue Expression Profile: Abundantly transcribed from the paternal allele in placental trophoblasts, fetal liver, embryonic mesoderm, and adult choroid plexus/leptomeninges (with adult hepatic promoter P1 turning on biallelically in humans, maintaining high lifelong plasma IGF-2 concentrations).
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Activates mitogenic and metabolic signaling through both the IGF-1 receptor (IGF1R) and the exon-11-skipped fetal isoform A of the insulin receptor (INSR-A), while being cleared and degraded in lysosomes upon binding the cation-independent mannose-6-phosphate/IGF2R scavenger receptor (which is reciprocally maternally expressed).
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Illustrates the kinship (parental conflict) theory of genomic imprinting: paternal ICR1 hypomethylation or paternal IGF2 loss-of-function mutations cause Silver-Russell syndrome (severe intrauterine and postnatal growth restriction, relative macrocephaly, body asymmetry), whereas maternal ICR1 hypermethylation or paternal uniparental disomy of 11p15.5 causes biallelic IGF2 overexpression and Beckwith-Wiedemann syndrome (macrosomia, macroglossia, omphalocele, hyperinsulinemic hypoglycemia, and predisposition to Wilms tumor WT1 and hepatoblastoma).
Therapeutic & Clinical Pharmacology: Soluble mesenchymal tumor overproduction of incompletely processed high-molecular-weight "big IGF-2" causes non-islet-cell tumor hypoglycemia (Doege-Potter syndrome), while hippocampal IGF-2 administration is studied for memory consolidation enhancement.