Insulin-like growth factor (IGF)-I, critical for all phases of human development and growth, mediates its action primarily through activation of the cell surface IGF-I receptor (IGF1R) signaling cascades. Recent identification of hypomorphic inactivating mutations in the IGF1R gene in children born SGA who failed to exhibit catch-up post-natal growth despite normal or elevated concentrations of circulating IGF-I, support the importance of the IGF-I-IGF1R system for both in utero and postnatal human growth. The overwhelming majority of proven pathophysiological IGF1R variants are heterozygous (including chromosomal copy number variants, CNV). Intriguingly, extremely rare autosomal recessive IGF1R mutations (two reported homozygous missense mutations and unreported homozygous mutations, currently under investigations), retained residual IGF1R expression/function.  Our goals are to better understand the spectrum of phenotype-genotype correlations and improve diagnosis, utilizing reconstitution systems, primary cellular studies, FACS analysis, iPSC models, knock-in mouse models.

Grant Funding: 
Cincinnati Children's Hospital Medical Center: Center of Pediatric Genomic (CpG) Award V.Hwa & T.Takebe (Co-PI)    Duration: 7/1/17 – 6/30/18
Title: Organoid models of endocrine growth disorder for personalized therapy testing
Goal: to assess the clinical utility of patient-based induced-PSC (iPSC) derived liver organoids for personalized therapeutic testing when abnormal hormonal responses are consequences of genetic defects
Role: Co-PI