IGF1R

Gene Facts

• HGNC Symbol: IGF1R (HGNC:5465)
• HGNC Name: insulin like growth factor 1 receptor
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: JTK13, CD221, IGFIR, MGC18216, IGFR
• %HI: 1.29
• pLI: 1
• LOEUF: 0.39
• Cytoband: 15q26.3
• Genomic Coordinates:

  GRCh37/hg19:	chr15:99191768-99507759
  GRCh38/hg38:	chr15:98648539-98964530

• MANE Select Transcript: NM_000875.5 ENST00000650285.1
• Function: Receptor tyrosine kinase which mediates actions of insulin- like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involved in cell growth and survival control. IGF1R is crucial for tumor transformation and survival of malignant cell. Ligand binding activates the receptor kinase, leading to receptor autophosphorylation, and tyrosines phosphorylation of multiple substrates, that function as signaling adapter proteins inc... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-11663
• ClinGen Curation ID: CCID:007315
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Related Links:
  15q26 (IGF1R)
• Last Evaluated: 11/08/2022

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• growth delay due to insulin-like growth factor I resistance

HI Evidence

• PUBMED: 14657428
  Abuzzahab et al. (2003) screened 42 patients with unexplained IUGR (intrauterine growth retardation) and subsequent short stature; another 50 children with short stature who had elevated circulating IGF-IR concentrations; as well as a control group of 43 children with normal birth weights. In the first cohort they identified one girl who was a compound heterozygote for Arg108Gln and Lys115Asn in exon 2 of the IGF-IR gene; in the second cohort one boy with a nonsense mutation (Arg59X) that reduced the number of IGF-I receptors on fibroblasts. His mother and half sib also had the mutation and were both small for gestational age at birth. The mother was reported to be short. Both children had intrauterine growth retardation and poor postnatal growth.
• PUBMED: 19240156
  Fang et al. (2009) reported a family (proband, mother, sib) with short stature with a 19 bp duplication in exon 18 which results in a premature termination codon at codon 1106 of the IGF1R open reading frame on one allele. Analyses of the primary dermal fibroblasts derived from the patient and family members indicated that the IGF1R mRNA expressed from the mutant allele was degraded through the nonsense-mediated mRNA decay pathway, resulting in reduced amount of wild-type IGF1R protein and, subsequently, diminished activation of the IGF1R pathway.
• PUBMED: 21811077
  Mohn et al. (2011) reported a family (proband, sister, 2 paternal aunts) with short stature and a nonsense mutation in IGF1R (Tyr387X). The affected individuals all present a variable degree of alterations in prenatal and postnatal growth and in carbohydrate metabolism.
• PUBMED: 25866162
  Fujimoto M et al., (2015) reported two patients of prenatal and postnatal growth retardation. One 8-year-old Japanese boy and another 3-year-old Japanese girl had two novel heterozygous nonsense mutations (p.Q1250X in boy and p.W1249X in girl). Heterozygous nonsense mutations affect the C-terminal region (p.Q1250X, p.W1249X) of IGF1R decreased the expression of IGF1R through the ERAD pathway demonstrating the importance of the C-terminal region and the dosage of this receptor for growth.
• PUBMED: 30848790
  Walenkamp MJE et al. (2019) reported IGF1R mutations in 41 of 335 patients in Netherlands. A total of 28 different variants including 14 missense, 3 nonsense, 3 frameshift, and 1 splice mutation were detected by Sanger sequencing. The nonsense and frameshift variants are c.58_59delTC p.Ser20Argfs*124; c.1093c>T p.Arg365*; c.3190C>TpArg1064* (2 patients); c.3454_3455delinsAAAATA p.Gly1152Lysfx*7; c.3631C>T p.Gln1211* and c.3759dup P.Lys1254Glnfx*120. The splice site variant, c.1828+1G>C, is predicted to affect splice donor site.
• PUBMED: 33113547
  Shapiro M et al., (2020) reported a family (twin probands of short stature and hypoglycemia, and two other family members of variable phenotypic expression had a heterozygous c.641-2A>G (p.Met214Thrfs*67) resulting in abnormal mRNA splicing and premature protein termination disrupting ligand-binding and membrane attachment in IGF1R gene. This novel loss-of-function mutation leads to aberrant mRNA splicing and IGF1R expression resulting in hypoglycemia, growth restriction, and altered immune phenotypes.

• HI Evidence Comments: Autosomal dominant mutations in IGF1R gene are reported to be associated with IGF1 insensitivity, in which the clinical presentation includes prenatal and postnatal growth failure, microcephaly, developmental delay (Mastromauro C and Chiarelli F 2022. PMID: 35949366.). Additional evidence includes: Kawashima-Sonoyayama Y et al., (2022) (PMID: 35431446) reported eight of the 11 patients who respond to GH therapy had heterozygous IGF1R mutations. The p.Arg739Gln mutation (Family A, proband and mother) resulted in a change in the cleavage site from Arg-Lys-Arg-Arg to Arg-Lys-Gln-Arg, which led to the failure of IGF1R proreceptor processing; The p.Arg461Leu mutation (Family B, proband and mother) is located in the L2 domain of the IGF1R α chain, leading to a decrease in the internalization of IGF1R. p.Asp1135Glu (Family C, proband and mother) leads to a defect in tyrosine phosphorylation of IGF1R and has a dominant negative effect on IGF1R. p.Gln1250* (Family D), p.Trp1249* (Family E), and p.Tyr888* (Family F, proband, sister and father) are nonsense mutations that lead to decreased or absent IGF1R protein expression. These findings resemble IGF1R haploinsufficiency. The p.Asp1135Glu mutation is considered the most severe missense mutation because of its dominant negative effect. The p.Asp1135Glu mutation is considered the most severe missense mutation because of its dominant negative effect. Veenma DCM et al. (2010) (PMID: 19955558) reported 0.095 Mb 15q26.3 interstitial microdeletion harboring part of the IGF1R gene, exons 11-21 of the IGF1R, in a Dutch family using MLPA (multiplex ligation dependent probe amplification. This deletion segregated with short height in seven out of 14 relatives across three generations. This intragenic IGF1R gene deletion/haploinsufficiency segregates with short height. Fadel IM et al. (2021) (PMID: 34322776) reported a heterozygous deletion of IGF1R (exons 4 through 21) in 1 out of the 40 children with pre- and postnatal growth restriction using multiplex ligation-dependent probe amplification (MLPA) to detect CNVs in IGF1R gene. Patients with heterozygous deletion involving IGF1R showed consistent growth restriction phenotype. LOF mutations that caused nonsense-mediated decay also result in the same consequence. Other references of interest include PMIDs: 24296753, 20962017, and 14671200.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: As no focal duplications of IGF1R have been reported, the triplosensitivity score of this gene is 0. However, evidence from multiple independent cases support the association of increased IGF1R copy number with overgrowth syndrome due to 15q terminal duplication. The definitive evidence is currently lacking to support that IGF1R alone is sufficient to cause overgrowth phenotype. Individuals and families with tall statue and overgrowth carry duplication of IGF1R gene resulted from unbalanced chromosome rearrangements involving 15q26.1 including IGF1R gene were reported, however, these cases all had other genetic abnormalities (Faivre L et al., 2002. PMID: 12404101; Nagai T et al., 2002. PMID 12407708; Kant SG et al., 2007. PMID: 17056309.). Relevant literature is summarized below: PMID 26689622: Leffler et al (2016) reported two familial microduplications of 15q26.3 causing overgrowth and variable intellectual disability with normal copy number of IGF1R, suggesting the possibility that the distal region of 15q contains another gene regulating human growth. PMID 19133692: Tatton-Brown et al. (2009) describe a case of 15q overgrowth syndrome caused by duplications of distal 15q, which include IGF1R. Additional references of interest include PMIDs: 14671200, 15164417, 12404101, and 22030053.