Functional effects of different types of CSF1R variants. (A) Before CSF1 binding (yellow square), CSF1 receptor (CSF1R) presents as a monomer on the cellular surface. In the presence of CSF1, CSF1R monomers undergo non-covalent dimerization (wild-type [WT]/WT) followed by autophosphorylation and signaling through activation of multiple kinase pathways including JNK.10 (B) Loss-of-function (LOF) variants (red stars) altering residues in the intracellular tyrosine kinase domain (TyrKD) impair the autophosphorylation of intracellular tyrosine residues required for downstream signaling, whereas it is unlikely that they affect the CSF1-dependent dimerization of CSF1R.4 Consequently, in the presence of WT monomers and monomers with a TyrKD mutation (WT/mutTyrKD), CSF1R should form in vivo WT homodimers (~25%), WT-mutant heterodimers (~50%), and mutant homodimers (~25%).2 The mutant CSF1R subunit of the dimer cannot phosphorylate the WT subunit, and also, by a dominant negative effect, should impair the phosphorylation activity of the normal subunit.2, 7 Therefore, in HLDS patients, the LOF should be ~75%, given that the nonfunctional mutant receptors are threefold in excess in comparison with the WT receptors.2 (C) The hypothesis illustrated in the subfigure B may explain why patients with CSF1R variants such as the p.Gln481*, which cause non-sense mediated RNA decay, do not develop HLDS. In these cases, where no WT mutant heterodimers exist, the LOF should be ~50%.2 (D) LOF mutations altering residues in the extracellular Ig-like domain (IgLD), as is the case for p.T79M or p.P132L variants,1, 4 likely affect the CSF1-dependent dimerization of CSF1R. Consequently, in the presence of WT monomers and monomers with an IgLD mutation (WT/mutIgLD), CSF1R should form in vivo only functional WT homodimers, the LOF will be ~50%, and the patients should not develop HLDS.4 HLDS, hereditary leukodystrophy with spheroids.