Dermal
neurofibromas (DNFs) are benign
peripheral nerve sheath tumors thought to originate from Schwann cell progenitors. These
tumors represent one of the hallmarks of the
neurofibromatosis type 1 (NF1)
tumor predisposition syndrome, where they can number in the thousands. While NF1-DNFs arise due to mutations in the NF1 gene, the vast majority of DNFs occur sporadically (sp-DNFs), where the genetic etiology is currently unknown. Herein, we employed whole-exome sequencing of sp-DNFs to identify a recurrent mutation in the KIR2DL5 gene, which codes for a
protein suppressor of natural killer (NK) cell activity. While the function of KIR2DL5 outside of the immune system is unknown, we identified a KIR2DL5N173D mutation in three of nine sp-DNFs, resulting in loss of KIR2DL5
protein expression. In contrast, two of these subjects had unrelated
tumors, which retained KIR2DL5
protein expression. Moreover, loss of KIR2DL5 expression was demonstrated in 15 of 45 independently-identified sp-DNFs. Consistent with its potential role as a negative growth regulator important for
neurofibroma maintenance, ectopic KIR2DL5N173D expression in normal human Schwann cells resulted in reduced KIR2DL5 expression and increased cell proliferation. Similarly, KIR2DL5
short hairpin RNA knockdown (KD) decreased KIR2DL5
protein levels and increased cell proliferation, as well as correlated with PDGFRβ and downstream RAS/AKT/mTOR hyperactivation. Importantly, inhibition of PDGFRβ or AKT/mTOR activity in KIR2DL5-KD human Schwann cells reduced proliferation to control levels. Collectively, these findings establish KIR2DL5 as a new Schwann cell growth regulator relevant to sp-DNF pathogenesis, which links sporadic and NF1-associated DNFs through RAS pathway hyperactivation.