Bi-allelic CSF1R Mutations Cause Skeletal Dysplasia of Dysosteosclerosis-Pyle Disease Spectrum and Degenerative Encephalopathy with Brain Malformation

Abstract

Colony stimulating factor 1 receptor (CSF1R) plays key roles in regulating development and function of the monocyte/macrophage lineage, including microglia and osteoclasts. Mono-allelic mutations of CSF1R are known to cause hereditary diffuse leukoencephalopathy with spheroids (HDLS), an adult-onset progressive neurodegenerative disorder. Here, we report seven affected individuals from three unrelated families who had bi-allelic CSF1R mutations. In addition to early-onset HDLS-like neurological disorders, they had brain malformations and skeletal dysplasia compatible to dysosteosclerosis (DOS) or Pyle disease. We identified five CSF1R mutations that were homozygous or compound heterozygous in these affected individuals. Two of them were deep intronic mutations resulting in abnormal inclusion of intron sequences in the mRNA. Compared with Csf1r-null mice, the skeletal and neural phenotypes of the affected individuals appeared milder and variable, suggesting that at least one of the mutations in each affected individual is hypomorphic. Our results characterized a unique human skeletal phenotype caused by CSF1R deficiency and implied that bi-allelic CSF1R mutations cause a spectrum of neurological and skeletal disorders, probably depending on the residual CSF1R function.

Microglial ERK signaling is a critical regulator of pro-inflammatory immune responses in Alzheimer’s disease

“…Csf1r is exclusively expressed by microglia in the brain and its inhibition leads to rapid depletion of homeostatic microglia in mouse models (Konno et al, 2018; Spangenberg et al, 2019). Moreover, Csf1r mutations in humans are associated with neurodegenerative disease conditions as well as abnormalities in brain development (Guo et al, 2019; Oosterhof et al, 2019). Mertk is a member of the TAM (Tyro3, Axl and Mertk) RTK family, is involved in phagocytic activity, and is primarily expressed by astrocytes and microglia in the brains of both humans and mice (Zhang et al, 2014).…”

Zebrafish macrophage developmental arrest underlies depletion of microglia and reveals Csf1r-independent metaphocytes

“…Zebrafish are particularly suitable to study immune cell development in vivo as they develop ex utero, are genetically tractable, and are transparent during early development (Ellett and Lieschke, 2010; Gore et al, 2018). We used our previously generated zebrafish line that is deficient for both csf1ra and csf1rb paralogs ( csf1r DM ), since the phenotypes of these fish, such as osteopetrosis and a lack of microglia, resemble those observed in mice, rats and humans (Caetano-Lopes et al, 2020; Chatani et al, 2011; Dai et al, 2002; Guo et al, 2019; Meireles et al, 2014; Oosterhof et al, 2019b; Oosterhof et al, 2018b; Pridans et al, 2018). The strong homology of basic developmental cellular processes has proven this model as indispensable for the identification of novel basic features of immune cell development and function (Barros-Becker et al, 2017; Bertrand et al, 2010a; Espin-Palazon et al, 2014; Kissa and Herbomel, 2010; Madigan et al, 2017; Tamplin et al, 2015; Tyrkalska et al, 2019).…”

A Novel Hypomorphic CSF1R Gene Mutation in the Biallelic State Leading to Fatal Childhood Neurodegeneration

“…Several of the patients described by Guo et al, including a 37-year-old woman who was diagnosed with osteopetrosis at age of 5 years, but did not experience any neurological symptoms until the third decade of life. 1,2 Dysmorphic facial features, such as long eyelashes, epicanthic folds, bulbous nose, dysplastic ears, and macrocephaly (þ5SD), have also been described in recessive form. 1,2 Patients with biallelic mutations can also have osteosclerosis of the craniofacial bones and skull, platyspondyly and abnormalities of the long bones, including undermodeling, widened metaphyses, and constricted and sclerotic diaphyses.…”

“…Compound heterozygosity for amorph (p.Gln481 Ã ) and hypomorph (p.Pro132Leu) led to Dandy-Walker syndrome and hydrocephalus requiring shunt at the age of 3 months with carrier adults having mild bone disease and dementia at 70 years. 1 Homozygosity for hypomorphic allele c.1969 þ 115_1969 þ 116del in intron 14 that affects a splicing regulatory site led to varying degrees of intellectual disability followed by childhood onset progressive encephalopathy at 14 to 23 years and milder bone disease. The carrier parents aged 70 and 69 years were normal clinically and on neuroimaging; thus, these alleles are also true recessive.…”

“…More recently, autosomal recessive mutations in the same gene have been described to underlie a novel phenotype encompassing pediatric-onset progressive brain disease and osteopetrosis. 1,2 We now report two siblings with childhood-onset neurodegeneration after an initial period of normal development likely due to a novel homozygous missense mutation in CSF1R.…”