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Title: Bi-allelic CSF1R Mutations Cause Skeletal Dysplasia of Dysosteosclerosis-Pyle Disease Spectrum and Degenerative Encephalopathy with Brain Malformation
Authors: GUO, LongBERTOLA, Debora RomeoTAKANOHASHI, AsakoSAITO, AsukaSEGAWA, YukoYOKOTA, TakanoriISHIBASHI, SatoruNISHIDA, YoichiroYAMAMOTO, Guilherme LopesFRANCO, Jose Francisco da SilvaHONJO, Rachel SayuriKIM, Chong AeMUSSO, Camila MansoTIMMONS, MargaretPIZZINO, AmyTAFT, Ryan J.LAJOIE, BryanKNIGHT, Melanie A.FISCHBECK, Kenneth H.SINGLETON, Andrew B.FERREIRA, Carlos R.WANG, ZhengYAN, LiGARBERN, James Y.SIMSEK-KIPER, Pelin O.OHASHI, HirofumiROBEY, Pamela G.BOYDE, AlanMATSUMOTO, NaomichiMIYAKE, NorikoSPRANGER, JuergenSCHIFFMANN, RaphaelVANDERVER, AdelineNISHIMURA, GenPASSOS-BUENO, Maria Rita dos SantosSIMONS, CasISHIKAWA, KinyaIKEGAWA, Shiro
Citation: AMERICAN JOURNAL OF HUMAN GENETICS, v.104, n.5, p.925-935, 2019
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.
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Artigos e Materiais de Revistas Científicas - FM/MPE
Departamento de Pediatria - FM/MPE

Artigos e Materiais de Revistas Científicas - HC/ICr
Instituto da Criança - HC/ICr

Artigos e Materiais de Revistas Científicas - LIM/03
LIM/03 - Laboratório de Medicina Laboratorial

Artigos e Materiais de Revistas Científicas - LIM/36
LIM/36 - Laboratório de Pediatria Clínica

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