Notably, mutations in the cSH2 domain, including the oncogenic truncation mutation (E601*) and the mutation affecting the phosphorylated peptide binding site (R649W) in SHORT syndrome, both lead to diminished sensitivity to PDGFR pY, underscoring the essential role of cSH2 in mediating effective PI3K signaling downstream of activated membrane receptors 51, 52. Here, CSH2 is linked to SHORT syndrome.