SH2B1

Gene Facts

• HGNC Symbol: SH2B1 (HGNC:30417)
• HGNC Name: SH2B adaptor protein 1
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: FLJ30542, SH2B
• %HI: 32.53
• pLI: 1
• LOEUF: 0.37
• Cytoband: 16p11.2
• Genomic Coordinates:

  GRCh37/hg19:	chr16:28857927-28885526
  GRCh38/hg38:	chr16:28846606-28874205

• MANE Select Transcript: NM_001387430.1 ENST00000684370.1
• Function: Adapter protein for several members of the tyrosine kinase receptor family. Involved in multiple signaling pathways mediated by Janus kinase (JAK) and receptor tyrosine kinases, including the receptors of insulin (INS), insulin-like growth factor I (IGF1), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), platelet-derived growth factor (PDGF) and fibroblast growth factors (FGFs). In growth hormone (GH) signaling, autophosphor... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-11221
• ClinGen Curation ID: CCID:007837
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Little Evidence for Haploinsufficiency (1)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Related Links:
  16p11.2 recurrent region (distal, BP2-BP3) (includes SH2B1)
• Last Evaluated: 07/13/2021

Haploinsufficiency (HI) Score Details

• HI Score: 1
• HI Evidence Strength: Little Evidence for Haploinsufficiency

HI Evidence

• PUBMED: 23160192
  Doche et al (2013) describe 4 heterozygous variants (1 frameshift and 3 missense) in SH2B1 detected in 5 apparently unrelated individuals of mixed European descent amongst a cohort of 300 individuals with severe, early-onset obesity with a disproportionate degree of insulin resistance for their obesity. Variants in genes causing known monogenic obesity syndromes had been excluded in these patients. All variants were inherited from overweight/obese parents. Individuals with SH2B1 variants were reported to have delayed speech development and aggressive behavior, but no formal psychiatric/behavioral observation was performed. The variants and the reported behavioral abnormalities were not detected amongst 500 control subjects. Subsequent functional studies demonstrated loss-of-function in assays of GH/NGF-mediated signaling but this doesn't rule out a gain of function or dominant-negative effect.
• PUBMED: 24971614
  Pearce et al (2014) describe 4 additional SH2B1 variants in 500 additional individuals from the same cohort of individuals with severe early-onset obesity used in the Doche et al. (2013) paper referenced above. Of these 4 new variants, only 1, T546A, lies within the same N-terminal region common to all 4 SH2B1 isoforms as the variants described in Doche et al. This variant was found in a single individual who was described as also having mild developmental delay. The other 3 variants are in the C-terminal tail of SH2B1 alpha; individuals with these variants were not reported to have neurodevelopmental phenotypes, and 2 of them have been observed in publically available exome databases (though BMI information is not available on these reportedly normal individuals). The authors suggest that "SH2B1 contains a spectrum of common and rare alleles that contribute to BMI and obesity predisposition with a broad range of penetrance, from low to more highly penetrant rare alleles." They also point out the "need to determine, at the mechanistic level, whether the behavioral phenotype results from disruption of a specific SH2B1 isoform (eg, SH2B1β) or a function emanating from the 1–631 region shared by all 4 isoforms."
• PUBMED: 17235396
  Ren et al (2007) generated Sh2b1-knockout mice that developed hyperlipidemia, leptin resistance, hyperphagia, obesity, hyperglycemia, insulin resistance, and glucose intolerance. Neuron-specific restoration of Sh2b1 corrected the metabolic disorders in the knockout mice and improved leptin signaling and leptin regulation of orexigenic neuropeptide expression in the hypothalamus. Neuron-specific overexpression of Sh2b1 dose-dependently protected against high fat diet-induced leptin resistance and obesity. They suggested that neuronal SH2B1 regulates energy balance, body weight, peripheral insulin sensitivity, and glucose homeostasis at least in part by enhancing hypothalamic leptin.
• PUBMED: 31439647
  Flores et al (2019) identified 15 SH2B1 variants in severely obese children. Four obesity-associated human SH2B1 variants lie in the Pleckstrin homology (PH) domain, suggesting that the PH domain is essential for SH2B1’s function. They generated a mouse model of a human variant in this domain (P322S). P322S/P322S mice exhibited substantial prenatal lethality. Examination of the P322S/+ metabolic phenotype revealed late-onset glucose intolerance.
• PUBMED: 26031769
  Aerts et al (2015) performed a mutation screen for variants in the SH2B1 coding region in 581 obese children and adolescents and 433 healthy, lean individuals with high-resolution melting curve analysis followed by direct sequencing, in the Belgian population. They found fifteen rare non-synonymous heterozygous variants. Several of these were found both in lean and obese subjects, suggesting that these are neutral polymorphisms. However, six private, heterozygous, non-synonymous variations were present in obese children only. They also identified six missense variants solely in lean individuals. They did not do any functional testing. They concluded that their results do not support disease causality.

• HI Evidence Comments: The SH2B1 gene has been associated with severe obesity, insulin resistance, and neurobehavioral abnormalities in mice and humans. The study by Aerts et al (2015) refutes this although reduced penetrance is reported. The SH2B1 gene lies within the recurrent (distal, BP2-BP3) 16p11.2 microdeletion region for which haploinsufficiency is known to be associated with obesity and neurobehavioral abnormalities with variable expressivity and reduced penetrance. Almost all reported pathogenic variants within SH2B1 alone are missense changes. As there are no reports of isolated whole gene deletions or confirmed loss of function variants we cannot rule out other disease mechanisms and/or environmental factors.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity