Bi-allelic CSF1R Mutations Cause Skeletal Dysplasia of Dysosteosclerosis-Pyle Disease Spectrum and Degenerative Encephalopathy with Brain Malformation
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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.
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Patients with homozygous CSF1R mutations can have a severe leukoencephalopathy with apparent congenital absence of microglia as well as skeletal dysplasia in some patients.
“Recent studies have described patients with homozygous CSF1R mutations causing a severe leukoencephalopathy with apparent congenital absence of microglia as well as skeletal dysplasia in some patients [15, 36].”
From Loss of homeostatic microglial phenotype in CSF1R-related Leukoencephalopathy (2020) · cites this paper as [15]
These individuals were found to have a novel syndrome due to biallelic variants in CSF1R characterized by brain malformation and skeletal dysplasia, reported in Guo et al. (2019).
“These individuals were found to have a novel syndrome due to biallelic variants in CSF1R characterized by brain malformation and skeletal dysplasia, reported in Guo et al. (2019).21”
From Genome sequencing in persistently unsolved white matter disorders (2020) · cites this paper as [21]
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Recent Advances in Basic Research for CSF1R-Microglial Encephalopathy
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Mechanisms and environmental factors shaping the ecosystem of brain macrophages
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Dysosteosclerosis: Clinical and Radiological Evolution Reflecting Genetic Heterogeneity
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Self-citationSLC4A2, another gene involved in acid-base balancing machinery of osteoclasts, causes osteopetrosis
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Major skull manifestations of skeletal dysplasias — pictorial essay
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Bone Disease Associated With Hereditary Diffuse Leukoencephalopathy With Spheroids
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- Authors
- Guo, L., Bertola, D. R., Takanohashi, A., Saito, A., Segawa, Y., Yokota, T., Ishibashi, S., Nishida, Y., Yamamoto, G. L., Franco, J. F. D. S., Honjo, R. S., Kim, C. A., Musso, C. M., Timmons, M., Pizzino, A., Taft, R. J., Lajoie, B., Knight, M. A., Fischbeck, K. H., Singleton, A. B., Ferreira, C. R., Wang, Z., Yan, L., Garbern, J. Y., Simsek-Kiper, P. O., Ohashi, H., Robey, P. G., Boyde, A., Matsumoto, N., Miyake, N., Spranger, J., Schiffmann, R., Vanderver, A., Nishimura, G., Passos-Bueno, M. R. D. S., Simons, C., Ishikawa, K., & Ikegawa, S.
- Affiliations
- RIKEN Center for Integrative Medical Sciences (JP)
- Universidade de São Paulo (BR)
- Children's Hospital of Philadelphia (US)
- Tokyo Medical and Dental University (JP)
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR)
- National Institutes of Health (US)
- Illumina (United States) (US)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Wayne State University (US)
- Saitama Children's Medical Center (JP)
- Queen Mary University of London (GB)
- Yokohama City University (JP)
- Greenwood Genetic Center (US)
- Baylor Scott & White Research Institute (US)
- Saitama University (JP)
- Royal Children's Hospital (AU)
- Corresponding author
- Bertola, Débora Romeo
- Ikegawa, Shiro
- ORCID
- Guo, Long
- Bertola, Débora Romeo
- Takanohashi, Asako
- Yokota, Takanori
- Ishibashi, Satoru
- Nishida, Yoichiro
- Yamamoto, Guilherme Lopes
- Honjo, Rachel Sayuri
- Kim, Chong Ae
- Musso, Camila Manso
- Pizzino, Amy
- Taft, Ryan J.
- Lajoie, Bryan
- Fischbeck, Kenneth H.
- Singleton, Andrew B.
- Ferreira, Carlos R.
- Wang, Zheng
- Ohashi, Hirofumi
- Robey, Pamela G.
- Boyde, Alan
- Matsumoto, Naomichi
- Miyake, Noriko
- Spranger, Jürgen
- Schiffmann, Raphael
- Vanderver, Adeline
- Nishimura, Gen
- Simons, Cas
- Ishikawa, Kinya
- Ikegawa, Shiro
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2019-05
- Volume
- 104
- Issue
- 5
- Pages
- 925-935
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC6507048
- OpenAlex
- W2937350838
- Cited by
- 133
- References
- 36
- Citations by year
- 2026: 16 · 2025: 13 · 2024: 17 · 2023: 11 · 2022: 21 · 2021: 21 · 2020: 25 · 2019: 9
- FWCI
- 6.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by-nc-nd)
- Funders
- National Health and Medical Research Council (NHMRC 1068278)
- Japan Agency for Medical Research and Development (14525125)
- Fundação de Amparo à Pesquisa do Estado de São Paulo (2015/21783-9/CEPID 2013/08028-1)
- Japan Society for the Promotion of Science (17K16710)
- Conselho Nacional de Desenvolvimento Científico e Tecnológico (304130/2016-8)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- CSF1R, biallelic variants, compound heterozygosity, skeletal dysplasia, hereditary diffuse leukoencephalopathy with spheroids, brain malformations, intronic variants, hypomorphic mutation, osteoclasts, microglia, monocyte/macrophage lineage, genotype-phenotype correlation
- MeSH terms
- Adolescent, Adult, Alleles, Animals, Brain, Child, Preschool, Female, Humans, Male, Mutation, Osteochondrodysplasias, Osteosclerosis, Phenotype, Receptor, Macrophage Colony-Stimulating Factor, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Mice, Knockout, Mice, Young Adult, Leukoencephalopathies
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