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

Long Guo; Débora Romeo Bertola; Asako Takanohashi; Asuka Saito; Yuko Segawa; Takanori Yokota; Satoru Ishibashi; Yoichiro Nishida; Guilherme Lopes Yamamoto; José Francisco da Silva Franco; Rachel Sayuri Honjo; Chong Ae Kim; Camila Manso Musso; Margaret Timmons; Amy Pizzino; Ryan J Taft; Bryan Lajoie; Melanie A Knight; Kenneth H Fischbeck; Andrew B Singleton; Carlos R Ferreira; Zheng Wang; Li Yan; James Y Garbern; Pelin O Simsek-Kiper; Hirofumi Ohashi; Pamela G Robey; Alan Boyde; Naomichi Matsumoto; Noriko Miyake; Jürgen Spranger; Raphael Schiffmann; Adeline Vanderver; Gen Nishimura; Maria Rita Dos Santos Passos-Bueno; Cas Simons; Kinya Ishikawa; Shiro Ikegawa

doi:10.1016/j.ajhg.2019.03.004

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

Am J Hum Genet. 2019 May 2;104(5):925-935. doi: 10.1016/j.ajhg.2019.03.004. Epub 2019 Apr 11.

Authors

Long Guo¹, Débora Romeo Bertola², Asako Takanohashi³, Asuka Saito⁴, Yuko Segawa⁵, Takanori Yokota⁴, Satoru Ishibashi⁴, Yoichiro Nishida⁴, Guilherme Lopes Yamamoto⁶, José Francisco da Silva Franco⁷, Rachel Sayuri Honjo⁷, Chong Ae Kim⁷, Camila Manso Musso⁸, Margaret Timmons⁹, Amy Pizzino³, Ryan J Taft¹⁰, Bryan Lajoie¹⁰, Melanie A Knight¹¹, Kenneth H Fischbeck¹¹, Andrew B Singleton¹², Carlos R Ferreira¹³, Zheng Wang¹⁴, Li Yan¹⁵, James Y Garbern¹⁶, Pelin O Simsek-Kiper¹⁷, Hirofumi Ohashi¹⁸, Pamela G Robey¹⁹, Alan Boyde²⁰, Naomichi Matsumoto²¹, Noriko Miyake²¹, Jürgen Spranger²², Raphael Schiffmann²³, Adeline Vanderver³, Gen Nishimura²⁴, Maria Rita Dos Santos Passos-Bueno⁸, Cas Simons²⁵, Kinya Ishikawa⁴, Shiro Ikegawa²⁶

Affiliations

¹ Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan.
² Unidade de Genética Clínica, Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-000, Brazil; Instituto de Biociências da Universidade de São Paulo, São Paulo 05508-090, Brazil. Electronic address: [email protected].
³ Division of Neurology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁴ Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
⁵ Department of Orthopedic Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
⁶ Unidade de Genética Clínica, Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-000, Brazil; Instituto de Biociências da Universidade de São Paulo, São Paulo 05508-090, Brazil.
⁷ Unidade de Genética Clínica, Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-000, Brazil.
⁸ Instituto de Biociências da Universidade de São Paulo, São Paulo 05508-090, Brazil.
⁹ Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
¹⁰ Illumina, Inc., 5200 Illumina Way, San Diego, CA 92122, USA.
¹¹ Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
¹² Laboratory of Neurogenetics, National Institute of Aging, NIH, Bethesda, MD 20892, USA.
¹³ Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA, and Division of Genetics and Metabolism, Children's National Health System, Washington, DC 20010, USA.
¹⁴ Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan; Department of Medical Genetics, Institute of Basic Medical Sciences, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100005, People's Republic of China.
¹⁵ Department of Neurology, China-Japan Friendship Hospital, Beijing 100029, People's Republic of China.
¹⁶ Center of Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA.
¹⁷ Department of Pediatrics, Hacettepe University Medical Faculty, Ankara 06100, Turkey.
¹⁸ Division of Medical Genetics, Saitama Children's Medical Center, Saitama 330-8777, Japan.
¹⁹ Skeletal Biology Section, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD 20892, USA.
²⁰ Biophysics, Oral Growth and Development, Dental Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
²¹ Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
²² Central German Competence Center for Rare Diseases (MKSE), Magdeburg 39120, Germany; Greenwood Genetic Center, Greenwood, SC 29646, USA.
²³ Baylor Scott & White Research Institute, Dallas, TX 75204, USA.
²⁴ Intractable Disease Center, Saitama University Hospital, Moro 350-0495, Japan.
²⁵ Translational Bioinformatics Group, Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC 3052, Australia; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
²⁶ Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan. Electronic address: [email protected].

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.

Keywords: CSF1R; HDLS; Pyle disease; dysosteosclerosis; leukoencephalopathy; mutation; osteoclast; osteosclerosis; skeletal dysplasia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Alleles
Animals
Brain / abnormalities*
Brain / metabolism
Brain / pathology
Child, Preschool
Female
Humans
Leukoencephalopathies / etiology*
Leukoencephalopathies / pathology
Male
Mice
Mice, Knockout
Mutation*
Osteochondrodysplasias / etiology*
Osteochondrodysplasias / pathology
Osteosclerosis / etiology*
Osteosclerosis / pathology
Phenotype
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / genetics*
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / physiology
Young Adult

Substances

CSF1R protein, human
Csf1r protein, mouse
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor

Supplementary concepts

Dysosteosclerosis
Hereditary Diffuse Leukoencephalopathy with Spheroids
Pyle disease

Grants and funding

U54 NS115052/NS/NINDS NIH HHS/United States