Guo L, Bertola DR, Takanohashi A, Saito A, Segawa Y, Yokota T, Ishibashi S, Nishida Y, Yamamoto GL, Franco JF, Honjo RS, Kim CA, Musso CM, Timmons M, Pizzino A, Taft RJ, Lajoie B, Knight MA, Fischbeck KH, Singleton AB, Ferreira CR, Wang Z, Yan L, Garbern JY, Simsek-Kiper PO, Ohashi H, Robey PG, Boyde A, Matsumoto N, Miyake N, Spranger J, Schiffmann R, Vanderver A, Nishimura G, Passos-Bueno MR, Simons C, Ishikawa K, Ikegawa S. Bi-allelic CSF1R Mutations Cause Skeletal Dysplasia of Dysosteosclerosis-Pyle Disease Spectrum and Degenerative Encephalopathy with Brain Malformation. Am J Hum Genet. 2019 May 2;104(5):925-935. Epub 2019 Apr 11 PubMed.

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  1. These two papers on CSF1R deficiency in humans are obviously rather interesting in the context of our own work. CSF1R mutations have been associated with the autosomal-dominant disease, hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS, or ALSP). Our earlier work showed that the coding mutations in this disease lead to an altered protein that lacks signalling functions and is a dominant-negative. It is dominant in two respects. The mutant protein forms inactive heterodimers with the normal gene product. So in an HDLS patient, only 25 percent of dimeric receptors are functional. Further, the nonfunctional receptors are still expressed on the cell surface, where they compete for ligand. We have made a mouse model of the human disease and confirmed that there is a dominant effect on macrophage biology and also that a homozygote is lethal (unpublished). Both these studies support the conclusion that individuals with a genuine heterozygous loss of function do not develop disease. The inheritance is recessive. By extension, haploinsufficiency is not the explanation for dominant inheritance of HDLS. We would suggest that in the very small number of cases where haploinsufficiency has been inferred there is some other form of dominant interference so that there is much more than 50 percent loss of CSF1R function.

    Interestingly Guo et al. also show that the mutants they have studied may not produce a 100 percent loss of CSF1R protein in their patients. So, they should not be compared directly to full knockouts in animal models. There are two misconceptions in both manuscripts. Firstly, there is no compelling evidence for functional expression of CSF1R outside the myeloid lineages. The small number of published studies of CSF1R expression in epithelia and neurons were disproved by later studies. So, the phenotypes observed in patients and animals are due to deficiencies in macrophage lineage cells. Secondly, the CSF1R mutation in mice is considerably less penetrant on the original mixed genetic background than in the inbred C57Bl6 genetic background. The heterozygous mutation in outbred mice has no effect (again arguing against haploinsufficiency) despite the fact that it is not dosage-compensated.

    The bone phenotypes observed by Guo et al. (largely due to the loss of osteoclasts) and brain phenotypes are similar to those observed in both receptor (CSF1R) and ligand (CSF1) mutations in both mice and rats. We recently published a knockout of CSF1R in rats (Pridans et al., 2018). These rats are born normally, and develop a postnatal growth retardation and osteopetrosis. They lack microglia entirely, and also share with the human patients a thinning of the corpus callosum and enlarged lateral ventricles. However, there is no loss of Cux1 mRNA in any brain region. By contrast to mutant inbred mice, many CSF1R knockout rats survive well into adulthood. The phenotype is variable and more penetrant in males. Since our published study, we have found that the impact of the CSF1R knockout in rats is also influenced by genetic background, being more severe on an inbred genetic background.

    There are also quite likely to be epistatic interactions in humans. For example, it is worth noting that  a variation at the Csf1 (ligand) locus associates with Paget’s disease in humans. We have also worked on novel CSF1R mutations in mice. We have recently generated a hypomorphic mutation associated with an enhancer deletion that entirely lacks microglia throughout development but has no brain phenotype. The mice are not osteopetrotic and grow normally. 

    The impacts of the CSF1R mutations in both Guo et al. and Oosterhof et al. are attributed to the loss of microglia. Our work suggests that dysregulation of peripheral macrophages is an essential contributor to brain pathology in CSF1R mutations and that microglia may actually be partly redundant.

    References:

    Pridans C, Raper A, Davis GM, Alves J, Sauter KA, Lefevre L, Regan T, Meek S, Sutherland L, Thomson AJ, Clohisey S, Bush SJ, Rojo R, Lisowski ZM, Wallace R, Grabert K, Upton KR, Tsai YT, Brown D, Smith LB, Summers KM, Mabbott NA, Piccardo P, Cheeseman MT, Burdon T, Hume DA. Pleiotropic Impacts of Macrophage and Microglial Deficiency on Development in Rats with Targeted Mutation of the Csf1r Locus. J Immunol. 2018 Nov 1;201(9):2683-2699. Epub 2018 Sep 24 PubMed.

    View all comments by Clare Pridans

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  1. Life Without Microglia: Rare Cases of CSF-1R Mutations Paint a Grim Picture