Modeling CSF‐1 receptor deficiency diseases – how close are we?

Chiţu, Violeta; Gökhan, Şölen; Stanley, E. Richard

doi:10.1111/febs.16085

Cited by 36 publications

(85 citation statements)

References 185 publications

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“…Importantly, in the older animals there was no evidence of astrocytosis that is commonly seen in neuroinflammation. The Csf1r E631K/+ mice are clearly different from Csf1r +/- mice (Chitu et al, 2020; Chitu et al, 2015; Chitu et al, 2021). The Csf1r ΔFIRE mutation, like the complete knockout, is not dosage compensated (Rojo et al, 2019).…”

Section: Discussionmentioning

confidence: 86%

“…Many ALSP patients present initially with sensorimotor deficiencies (Chitu et al, 2021; Konno et al, 2018; Konno et al, 2017) and CSF1R signalling has been directly implicated in neuropathic pain (Saleh et al, 2018). To seek evidence of these symptoms in the Csf1r E631K/+ mice, we performed a wide range of sensorimotor tests.…”

Section: Resultsmentioning

confidence: 99%

“…Upon ligand binding, CSF1R dimerization and autophosphorylation generates phosphotyrosine motifs that act as docking sites for multiple downstream effector pathways (Chitu and Stanley, 2017; Stanley and Chitu, 2014). Biallelic recessive loss-of-function mutations in mouse, rat and human CSF1R genes are causally linked to osteopetrosis and postnatal developmental abnormalities (reviewed in (Chitu et al, 2021; Hume et al, 2020)). In 2011, Rademakers et al (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).…”

Section: Introductionmentioning

confidence: 99%

“…Biallelic recessive loss-of-function mutations in mouse, rat and human CSF1R genes are causally linked to osteopetrosis and postnatal developmental abnormalities (reviewed in (Chitu et al, 2021; Hume et al, 2020)). In 2011, Rademakers et al (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 that time, more than 100 different disease-associated CSF1R coding mutations have been identified (Chitu et al, 2021; Guo and Ikegawa, 2021; Konno et al, 2018; Konno et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…In 2011, Rademakers et al (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 that time, more than 100 different disease-associated CSF1R coding mutations have been identified (Chitu et al, 2021; Guo and Ikegawa, 2021; Konno et al, 2018; Konno et al, 2017). Characteristic features of ALSP include enlarged ventricles, cerebral atrophy, periventricular calcifications and thinning of the corpus callosum (Konno et al, 2018; Konno et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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

Stables

Sehgal

et al. 2021

Preprint

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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 (Glu631Lys; 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 expands tissue macrophage populations in controls. In the brain, microglial cell numbers and dendritic arborization were reduced in the Csf1rE631K/+ mice as in ALSP patients. 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 disease-associated CSF1R mutations encode dominant negative repressors of CSF1R signaling. We speculate that leukoencephalopathy associated with human CSF1R mutations requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles.

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Section: Discussionmentioning

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Stables

Sehgal

et al. 2021

Preprint

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Clinical, genetic, and molecular characteristics in a central‐southern Chinese cohort of genetic leukodystrophies

Yan

et al. 2023

Ann Clin Transl Neurol

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ObjectiveLeukodystrophies are a diverse group of rare inherited disorders that affect the white matter of the central nervous system with a wide phenotypic spectrum. We aimed to characterize the clinical and genetic features of leukodystrophies in a central‐southern Chinese cohort.MethodsA cohort of 16 Chinese probands with leukodystrophy was recruited and performed genetic analysis by targeted panels or whole‐exome sequencing. Further functional analysis of identified mutations in the colony stimulating factor 1 receptor (CSF1R) gene was explored.ResultsA total of eight pathogenic variants (3 novel, 5 documented) were identified in genes including AARS2, ABCD1, CSF1R, and GALC. Common symptoms of leukodystrophy such as cognitive decline, behavioral symptoms, bradykinesia, and spasticity were observed in mutation carriers as well as other rare features (e.g., seizure, dysarthric, and vision impairment). Overexpressing CSF1R mutants p.M875I and p.F971Sfs*7 in vitro showed pronounced cleavage CSF1R and suppressed protein expression, respectively, and reduced transcripts of both mutants were observed. CSF1 treatment revealed deficient and suppressed CSF1R phospho‐activation with the mutants. In contrast to the plasma membrane and endoplasmic reticulum (ER) localized wild‐type CSF1R, M875I mutant showed much less membrane association and greater detainment in the ER, whereas F971Sfs*7 mutation led to aberrant non‐ER localization. Both mutations caused suppressed cell viability, which was partially resulted from deficient/suppressed CSF1R‐ERK signaling.InterpretationIn summary, our findings expand the mutation spectrum of these genes in leukodystrophies. Supported by in vitro validation of the pathogenicity of heterozygous CSF1R mutations, our data also provide insights into the pathogenic mechanisms of CSF1R‐related leukodystrophy.

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Leukoencephalopathy with calcifications, developmental brain abnormalities and skeletal dysplasia due to homozygosity for a hypomorphic CSF1R variant: A report of three siblings

Beerepoot,

Verbeke,

Plantinga

et al. 2024

American J of Med Genetics Pt A

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We report three siblings homozygous for CSF1R variant c.1969 + 115_1969 + 116del to expand the phenotype of “brain abnormalities, neurodegeneration, and dysosteosclerosis” (BANDDOS) and discuss its link with “adult leukoencephalopathy with axonal spheroids and pigmented glia” (ALSP), caused by heterozygous CSF1R variants. We evaluated medical, radiological, and laboratory findings and reviewed the literature. Patients presented with developmental delay, therapy‐resistant epilepsy, dysmorphic features, and skeletal abnormalities. Secondary neurological decline occurred from 23 years in sibling one and from 20 years in sibling two. Brain imaging revealed multifocal white matter abnormalities and calcifications during initial disease in siblings two and three. Developmental brain anomalies, seen in all three, were most severe in sibling two. During neurological decline in siblings one and two, the leukoencephalopathy was progressive and had the MRI appearance of ALSP. Skeletal survey revealed osteosclerosis, most severe in sibling three. Blood markers, monocytes, dendritic cell subsets, and T‐cell proliferation capacity were normal. Literature review revealed variable initial disease and secondary neurological decline. BANDDOS presents with variable dysmorphic features, skeletal dysplasia, developmental delay, and epilepsy with on neuro‐imaging developmental brain anomalies, multifocal white matter abnormalities, and calcifications. Secondary neurological decline occurs with a progressive leukoencephalopathy, in line with early onset ALSP. Despite the role of CSF1R signaling in myeloid development, immune deficiency is absent. Phenotype varies within families; skeletal and neurological manifestations may be disparate.

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Modeling CSF‐1 receptor deficiency diseases – how close are we?

Cited by 36 publications

References 185 publications

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

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

Clinical, genetic, and molecular characteristics in a central‐southern Chinese cohort of genetic leukodystrophies

Leukoencephalopathy with calcifications, developmental brain abnormalities and skeletal dysplasia due to homozygosity for a hypomorphic CSF1R variant: A report of three siblings

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