The DOI matches its Crossref record; 34 of the 36 references it cites were found in a registry or an index.
Bi-allelic CSF1R Mutations Cause Skeletal Dysplasia of Dysosteosclerosis-Pyle Disease Spectrum and Degenerative Encephalopathy with Brain Malformation
Open accessAbstract
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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
In the citing paper
“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]
Citations
Cites
Dai, X.-M., Ryan, G. R., Hapel, A. J., Dominguez, M. G., Russell, R. G., Kapp, S., Sylvestre, V., & Stanley, E. R. (2002) · Blood · doi:10.1182/blood.v99.1.111 · Cited by 1,184
Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy
Cannarile, M. A., Weisser, M., Jacob, W., Jegg, A.-M., Ries, C. H., & Rüttinger, D. (2017) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-017-0257-y · Cited by 1,046
CSF-1 regulation of the wandering macrophage: complexity in action
Pixley, F. J., & Stanley, E. R. (2004) · Trends in Cell Biology · doi:10.1016/j.tcb.2004.09.016 · Cited by 807
Erblich, B., Zhu, L., Etgen, A. M., Dobrenis, K., & Pollard, J. W. (2011) · PLoS ONE · doi:10.1371/journal.pone.0026317 · Cited by 649
Rademakers, R., Baker, M., Nicholson, A. M., Rutherford, N. J., Finch, N., Soto-Ortolaza, A., Lash, J., Wider, C., Wojtas, A., DeJesus-Hernandez, M., et al. (2012) · Nature Genetics · doi:10.1038/ng.1027 · Cited by 571
Self-citationNosology and classification of genetic skeletal disorders: 2015 revision
Bonafe, L., Cormier‐Daire, V., Hall, C., Lachman, R., Mortier, G., Mundlos, S., Nishimura, G., Sangiorgi, L., Savarirayan, R., Sillence, D., et al. (2015) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.37365 · Cited by 569
Self-citationOlmos-Alonso, A., Schetters, S. T. T., Sri, S., Askew, K., Mancuso, R., Vargas-Caballero, M., Holscher, C., Perry, V. H., & Gomez-Nicola, D. (2016) · Brain · doi:10.1093/brain/awv379 · Cited by 532
Arceci, R. J., Shanahan, F., Stanley, E. R., & Pollard, J. W. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.22.8818 · Cited by 272
Distribution of cells bearing receptors for a colony-stimulating factor (CSF-1) in murine tissues.
Byrne, P. V., Guilbert, L. J., & Stanley, E. R. (1981) · The Journal of Cell Biology · doi:10.1083/jcb.91.3.848 · Cited by 237
CSF-1 signals directly to renal tubular epithelial cells to mediate repair in mice
Weinmann‐Menke, J., Iwata, Y., Rabacal, W., Basu, R., Yeung, Y.-G., Humphreys, B. D., Wada, T., Schwarting, A., Stanley, E. R., & Kelley, V. R. (2009) · Journal of Clinical Investigation · doi:10.1172/jci39087 · Cited by 172
Research works printed but not linked: 1
- Edwin, 1931, A case of unusual bone development, JBJS, 13, 874
Cited by
Sorted by citations
Items 101–134 of 134
Adult‐onset leukoencephalopathy caused by CSF1R mutations: Is all that glitters gold?
Salsano, E., & Benzoni, C. (2022) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.51490 · Cited by 3
Khodabakhsh, P., & Garaschuk, O. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27031185 · Cited by 3
Cho, D. K., Lee, H.-M., Kim, J. A., Song, J. G., Hwang, S.-H., Lee, B., Park, J., Tran, K. M., Kim, J., Vo, P. N. L., et al. (2024) · Database · doi:10.1093/database/baae085 · Cited by 2
Liu, B., Zhao, S., Yan, Z., Zhao, L., Lin, J., Wang, S., Niu, Y., Li, X., Qiu, G., study, D. D. I. S. A. C. (., et al. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.641133 · Cited by 2
Glial Origins of Inherited White Matter DisordersPreprint
Sevagamoorthy, A., Vanderver, A. L., Fraser, J. L., & Orthmann‐Murphy, J. L. (2024) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a041457 · Cited by 2
Self-citationChi, L., Tu, H., Li, Z., Qiu, L., Zhang, Z., Chia, S., Tan, J. Y., Ho, I. A. W., Loh, Y., Tan, E., et al. (2026) · Cell Death Discovery · doi:10.1038/s41420-026-02995-2 · Cited by 1
The pathogenesis and intersecting mechanisms of monogenic bone mass disorders
Padidela, R., Hendrickx, G., Mortier, G. R., & Mäkitie, O. (2026) · Nature Reviews Endocrinology · doi:10.1038/s41574-026-01260-x · Cited by 1
Liu, Y., Jacquelin, S., Taylor, I., Green, E. K., Patkar, O. L., Keshvari, S., Ranpura, G. N., O’Brien, C. J. O., Jessen, E. E., Maxwell, E. L., et al. (2026) · Development · doi:10.1242/dev.205655 · Cited by 1
CSF1R-dependent macrophages control B cell development and function in the chicken immune system
Wu, Z., Harne, R., Idoko-Akoh, A., Foschi, F., Meddle, S., Macdonald, J., Shih, B. B.-J., McGrew, M. J., Hume, D. A., & Balic, A. (2026) · The Journal of Immunology · doi:10.1093/jimmun/vkag143 · Cited by 1
Macrophages in embryonic development
Mariani, S. A., Vaughan, H. J., Doyle, E. H., & Gordon, S. (2026) · Nature reviews. Immunology · doi:10.1038/s41577-026-01327-w · Cited by 1
Chen, F., Wei, R., Wang, Y., Cao, Q., Wang, J., Wang, C., Yao, D., Yao, Z., Ni, C., & Li, M. (2025) · npj Genomic Medicine · doi:10.1038/s41525-025-00466-8 · Cited by 1
Stem cell transplant arrests decline in case of CSF1R leukoencephalopathy
Lynch, D. S., & Houlden, H. (2019) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2019-321021 · Cited by 1
Osteoclasts in Skeletal Diseases
Sun, Q., Adamik, J., & Galson, D. L. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.11168-7 · Cited by 1
Stables, J., Green, E. K., Sehgal, A., Patkar, O. L., Keshvari, S., Taylor, I., Ashcroft, M. E., Grabert, K., Wollscheid-Lengeling, E., Szymkowiak, S., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.09.29.462493 · Cited by 1
Sehgal, A., Carter‐Cusack, D., Keshvari, S., Patkar, O. L., Huang, S., SUMMERS, K. M., Hume, D. A., & Irvine, K. M. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.02.19.529164 · Cited by 1
Microglia are not required for normal postnatal brain development and cognitive function in the ratPreprint
Green, E. K., Li, X., Guo, Y., Carter‐Cusack, D., Rojo, R., Lyall, M., Bell, A., Zheng, H., Teenan, O., Till, S. M., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.22.694658 · Cited by 1
Rosenstein, I., Andersen, O., Daniel, V., Englund, E. M., Granberg, T., Hedberg‐Oldfors, C., Jood, K., Fitrah, Y. A., Ikeuchi, T., & Karrenbauer, V. D. (2021) · Research Square · doi:10.21203/rs.3.rs-718394/v1
Osteopetrosis: Gene-Based Nosology and Significance SLC29A3, DysosteosclerosisPreprint
Turan, S. (2022) · SSRN Electronic Journal · doi:10.2139/ssrn.4178843
Li, X., Liu, J., & Liu, C. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.937362
Verkhratsky, A., & Butt, A. M. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-821565-4.00005-5
Clinical meaning of high bone mineral density (Part I). Genetic diseases causing high bone mass
Skripnikova, I. A., Тамерланович, Ц. Т., & Polyakova, E. Y. (2024) · Osteoporosis and Bone Diseases · doi:10.14341/osteo13170
Disorders of Bone Density, Volume, and Mineralization
Pyeritz, R. E. (2024) · Elsevier eBooks · doi:10.1016/b978-0-12-812531-1.00022-1
Untangling the Genetic Threads of Alzheimer's: Insights into Risk Factors and Biomarkers
Naiyeri, A., Moqadami, A., & Khalaj‐Kondori, M. (2025) · Current Gene Therapy · doi:10.2174/0115665232338503241227111640
Etude de l'impact d'une déficience en interleukine-34 sur le développement et les réponses immunes
Freuchet, A. (2019) · theses.fr (ABES) · doi:10.70675/0ae4fc4az1469z476ez801fzb3b0ae6f572b
Mesaoudi, A. E. (2024) · theses.fr (ABES) · doi:10.70675/f339157ez1688z4acaz87fcz0ecae062a7cc
CSF1R+ Macrophages and Osteoclasts Are Essential for Limb Bone Development During Embryogenesis
Ma, F., Zhou, R., Rosin, M., & Rosin, J. M. (2026) · Journal of Developmental Biology · doi:10.3390/jdb14030031
CSF1R-related leukoencephalopathy: experimental models and potential for treatment
Hume, D. A., & Irvine, K. M. (2026) · Disease Models & Mechanisms · doi:10.1242/dmm.052957
Pyle disease – Functional validation of disease-causing missense variants in SFRP4/sFRP4
Magnus, L., Hordyjewska‐Kowalczyk, E., Sowińska‐Seidler, A., Ryhänen, E., Jamsheer, A., Mortier, G. R., Mäkitie, O., & Hendrickx, G. (2026) · Bone · doi:10.1016/j.bone.2026.118037
Macrophages Promote Vascular Maturation to Support Tooth Germ Morphogenesis
Wang, Z., Wang, M., Wang, S., Wang, J., Zhang, Y., Wang, J., Wang, L., Liu, J., Zhao, D., Zhang, Z., et al. (2026) · Journal of Dental Research · doi:10.1177/00220345261470395
Self-citationColony‐stimulating factor 1 receptor‐related disorder: Clinical variability of biallelic variants
Milanowski, Ł., de Souza, J., Santos, M. L. S. F., Teive, H. A. G., Fink, J. K., Orthmann‐Murphy, J. L., Arnold, K., Dulski, J., CSF1R‐RD Study Group, & Wszołek, Z. K. (2026) · Developmental Medicine & Child Neurology · doi:10.1111/dmcn.70515
Microglial GRB2 is essential for brain ventriculogenesis and cerebrospinal fluid homeostasis
Duy, P. Q., Reeves, B. C., Sun, H., Peng, X., Kalailingam, P., Allington, G., Dennis, E., Hao, L. T., Wang, L., Rufino‐Ramos, D., et al. (2026) · Journal of Clinical Investigation · doi:10.1172/jci185791
Chen, X., Li, X., Gu, Z., Lu, Q., Qian, X., Fan, Y., Deng, K., Li, S., Wei, Z., Xu, Y., et al. (2026) · Bone Research · doi:10.1038/s41413-026-00565-x
Wallace, E. R., Block, C. K., & Rush, B. K. (2026) · Neurocase · doi:10.1080/13554794.2026.2757240
Metadata
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
