Homozygous Mutations in CSF1R Cause a Pediatric-Onset Leukoencephalopathy and Can Result in Congenital Absence of Microglia

Am J Hum Genet. 2019 May 2;104(5):936-947. doi: 10.1016/j.ajhg.2019.03.010.

Nynke Oosterhof ¹, Irene J Chang ², Ehsan Ghayoor Karimiani ³, Laura E Kuil ¹, Dana M Jensen ⁴, Ray Daza ⁵, Erica Young ⁵, Lee Astle ⁶, Herma C van der Linde ¹, Giridhar M Shivaram ⁷, Jeroen Demmers ⁸, Caitlin S Latimer ⁹, C Dirk Keene ⁹, Emily Loter ¹⁰, Reza Maroofian ¹¹, Tjakko J van Ham ¹², Robert F Hevner ¹³, James T Bennett ¹⁴

Affiliations

1 Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.
2 Department of Pediatrics, Division of Genetic Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.
3 Genetics Research Centre, Molecular and Clinical Sciences Institute, St George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
4 Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA.
5 Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
6 Department of Laboratory and Pathology, Alaska Native Medical Center, Anchorage, AK 99508, USA.
7 Department of Radiology, Seattle Children's Hospital, Seattle, WA 98105.
8 Proteomics Center, Erasmus University Medical Center, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.
9 Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA.
10 Department of Laboratories, Seattle Children's Hospital, Seattle, WA 98105, USA.
11 Genetics Research Centre, Molecular and Clinical Sciences Institute, St George's, University of London, Cranmer Terrace, London SW17 0RE, UK; Department of Neuromuscular Disorders and Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
12 Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands. Electronic address: [email protected].
13 Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA.
14 Department of Pediatrics, Division of Genetic Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA; Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA. Electronic address: [email protected].

PMID: 30982608 DOI: 10.1016/j.ajhg.2019.03.010

Abstract

Microglia are CNS-resident macrophages that scavenge debris and regulate immune responses. Proliferation and development of macrophages, including microglia, requires Colony Stimulating Factor 1 Receptor (CSF1R), a gene previously associated with a dominant adult-onset neurological condition (adult-onset leukoencephalopathy with axonal spheroids and pigmented glia). Here, we report two unrelated individuals with homozygous CSF1R mutations whose presentation was distinct from ALSP. Post-mortem examination of an individual with a homozygous splice mutation (c.1754-1G>C) demonstrated several structural brain anomalies, including agenesis of corpus callosum. Immunostaining demonstrated almost complete absence of microglia within this brain, suggesting that it developed in the absence of microglia. The second individual had a homozygous missense mutation (c.1929C>A [p.His643Gln]) and presented with developmental delay and epilepsy in childhood. We analyzed a zebrafish model (csf1r^DM) lacking Csf1r function and found that their brains also lacked microglia and had reduced levels of CUX1, a neuronal transcription factor. CUX1⁺ neurons were also reduced in sections of homozygous CSF1R mutant human brain, identifying an evolutionarily conserved role for CSF1R signaling in production or maintenance of CUX1⁺ neurons. Since a large fraction of CUX1⁺ neurons project callosal axons, we speculate that microglia deficiency may contribute to agenesis of the corpus callosum via reduction in CUX1⁺ neurons. Our results suggest that CSF1R is required for human brain development and establish the csf1r^DM fish as a model for microgliopathies. In addition, our results exemplify an under-recognized form of phenotypic expansion, in which genes associated with well-recognized, dominant conditions produce different phenotypes when biallelically mutated.

Keywords

CSF1R; CUX1; agenesis corpus callosum; axonal spheroids; leukoencephalopathy; microglia; neuropathology; osteopetrosis; recessive; zebrafish.

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