From HDLS to BANDDOS: fast-expanding phenotypic spectrum of disorders caused by mutations in CSF1R

Guo, Long; Ikegawa, Shiro

doi:10.1038/s10038-021-00942-w

Cited by 22 publications

(18 citation statements)

References 34 publications

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“…Neither the microgliosis phenotype nor changes in microglia-specific gene expression was replicated in Csf1r +/− rats ( Patkar et al, 2021a ). Similarly, there is no reported evidence of neuropathology in aged obligate carriers of recessive CSF1R loss-of-function alleles in humans ( Guo et al, 2019 ; Guo and Ikegawa, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…In 2011, Rademakers et al (2011) reported heterozygous amino acid substitutions in the tyrosine kinase domain of CSF1R in patients with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), now also called CSF1R-related leukoencephalopathy (CRL) ( Chitu et al, 2021 ). Since then, more than 100 different disease-associated CSF1R coding mutations have been identified ( Chitu et al, 2021 ; Guo and Ikegawa, 2021 ; Konno et al, 2018 , 2017 ). Characteristic features of ALSP include enlarged ventricles, cerebral atrophy, periventricular calcifications and thinning of the corpus callosum ( Konno et al, 2018 , 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant inhibitory impact on CSF1R signalling

et al. 2022

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Amino acid substitutions in the kinase domain of the human CSF1R gene are associated with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). To model the human disease, we created a disease-associated mutation (pGlu631Lys; E631K) in the mouse Csf1r locus. Homozygous mutation (Csf1rE631K/E631K) phenocopied the Csf1r knockout, with prenatal mortality or severe postnatal growth retardation and hydrocephalus. Heterozygous mutation delayed the postnatal expansion of tissue macrophage populations in most organs. Bone marrow cells from Csf1rE631K/+mice were resistant to CSF1 stimulation in vitro, and Csf1rE631K/+ mice were unresponsive to administration of a CSF1-Fc fusion protein, which expanded tissue macrophage populations in controls. In the brain, microglial cell numbers and dendritic arborisation were reduced in Csf1rE631K/+ mice, as in patients with ALSP. The microglial phenotype is the opposite of microgliosis observed in Csf1r+/− mice. However, we found no evidence of brain pathology or impacts on motor function in aged Csf1rE631K/+ mice. We conclude that heterozygous disease-associated CSF1R mutations compromise CSF1R signalling. We speculate that leukoencephalopathy associated with dominant human CSF1R mutations requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant inhibitory impact on CSF1R signalling

et al. 2022

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“…Actually, using the NeuroChip, Blauwendraat et al (2019) analyzed rare variants of damaging mutations in 1243 autopsy-confirmed neurodegenerative cases that were diagnosed as AD, FTD or ALS in the Johns Hopkins Brain Resource Center, and identified 2 cases with a pathogenic CSF1R mutation (p.G589E, and p.M755T or M766T) and 1 case with a likely pathogenic CSF1R mutation (p.L868P). Thus, there are complex genotype-phenotype associated with ALSP (Guo and Ikegawa, 2021). Nonetheless, the number of ALSP patients confirmed by genetic diagnosis of CSF1R has been increasing in various populations.…”

Section: Csf1r In Neurodegenerative Diseasesmentioning

confidence: 99%

Insights Into the Role of CSF1R in the Central Nervous System and Neurological Disorders

Duan

Wang

et al. 2021

Front. Aging Neurosci.

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The colony-stimulating factor 1 receptor (CSF1R) is a key tyrosine kinase transmembrane receptor modulating microglial homeostasis, neurogenesis, and neuronal survival in the central nervous system (CNS). CSF1R, which can be proteolytically cleaved into a soluble ectodomain and an intracellular protein fragment, supports the survival of myeloid cells upon activation by two ligands, colony stimulating factor 1 and interleukin 34. CSF1R loss-of-function mutations are the major cause of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and its dysfunction has also been implicated in other neurodegenerative disorders including Alzheimer’s disease (AD). Here, we review the physiological functions of CSF1R in the CNS and its pathological effects in neurological disorders including ALSP, AD, frontotemporal dementia and multiple sclerosis. Understanding the pathophysiology of CSF1R is critical for developing targeted therapies for related neurological diseases.

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“…Over the past 20 years, several unrelated families presenting with inherited adult-onset leukodystrophy and pathological neuroaxonal spheroids and pigmented glia have been reported ( Köhler et al, 2018 ). These conditions have been known by a series of names ranging from the initial terms POLD and HDLS to the more recent term adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) ( Konno et al, 2018a ; Guo and Ikegawa, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Two Novel Intronic Mutations in the CSF1R Gene in Two Families With CSF1R-Microglial Encephalopathy

Jiang

Wang

et al. 2022

Front. Cell Dev. Biol.

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Objective: To describe two novel heterozygous splicing variants of the CSF1R gene responsible for CSF1R-microglial encephalopathy in two unrelated Han Chinese families and further explore the relationship between the pathological and neuroimaging findings in this disease.Methods: The demographic data, detailed medical history, and clinical manifestations of two unrelated Han families with CSF1R-microglial encephalopathy were recorded. Some family members also underwent detailed neuropsychological evaluation, neuroimaging, and genetic testing. The probands underwent whole-exome sequencing (WES) or next-generation sequencing (NGS) to confirm the diagnosis. The findings were substantiated using Sanger sequencing, segregation analysis, and phenotypic reevaluation.Results: Both families presented with a dominant hereditary pattern. Five of 27 individuals (four generations) from the first family, including the proband and his sister, father, uncle, and grandmother, presented with cognitive impairments clinically during their respective lifetimes. Brain magnetic resonance imaging (MRI) depicted symmetric, confluent, and diffuse deep white matter changes, atrophy of the frontoparietal lobes, and thinning of the corpus callosum. The proband’s brother remained asymptomatic; brain MRI revealed minimal white matter changes, but pseudo-continuous arterial spin labeling (pCASL) demonstrated a marked reduction in the cerebral blood flow (CBF) in the bilateral deep white matter and corpus callosum. Seven family members underwent WES, which identified a novel splice-site heterozygous mutation (c.2319+1C>A) in intron 20 of the CSF1R gene in four members. The proband from the second family presented with significant cognitive impairment and indifference; brain MRI depicted symmetric diffuse deep white matter changes and thinning of the corpus callosum. The proband’s mother reported herself to be asymptomatic, while neuropsychological evaluation suggested mild cognitive impairment, and brain MRI demonstrated abnormal signals in the bilateral deep white matter and corpus callosum. NGS of 55 genes related to hereditary leukodystrophy was performed for three members, which confirmed a novel splice-site heterozygous mutation (c.1858+5G>A) in intron 13 of the CSF1R gene in two members.Conclusions: Our study identified two novel splicing mutation sites in the CSF1R gene within two independent Chinese families with CSF1R-microglial encephalopathy, broadening the genetic spectrum of CSF1R-microglial encephalopathy and emphasizing the value of pCASL for early detection of this disease.

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From HDLS to BANDDOS: fast-expanding phenotypic spectrum of disorders caused by mutations in CSF1R

Cited by 22 publications

References 34 publications

A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant inhibitory impact on CSF1R signalling

A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant inhibitory impact on CSF1R signalling

Insights Into the Role of CSF1R in the Central Nervous System and Neurological Disorders

Two Novel Intronic Mutations in the CSF1R Gene in Two Families With CSF1R-Microglial Encephalopathy

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