@article{abc97e7831404342b64e6b44b1e2848d,
title = "Identification and functional characterization of novel mutations including frameshift mutation in exon 4 of CSF1R in patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia",
abstract = "Objective: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is caused by mutations in CSF1R. Pathogenic mutations in exons 12–22 including coding sequence of the tyrosine kinase domain (TKD) of CSF1R were previously identified. We aimed to identify CSF1R mutations in patients who were clinically suspected of having ALSP and to determine the pathogenicity of novel CSF1R variants. Methods: Sixty-one patients who fulfilled the diagnostic criteria of ALSP were included in this study. Genetic analysis of CSF1R was performed for all the coding exons. The haploinsufficiency of CSF1R was examined for frameshift mutations by RT-PCR. Ligand-dependent autophosphorylation of CSF1R was examined in cells expressing CSF1R mutants. Results: We identified ten variants in CSF1R including two novel frameshift, five novel missense, and two known missense mutations as well as one known missense variant. Eight mutations were located in TKD. One frameshift mutation (p.Pro104LeufsTer8) and one missense variant (p.His362Arg) were located in the extracellular domain. RT-PCR analysis revealed that the frameshift mutation of p.Pro104LeufsTer8 caused nonsense-mediated mRNA decay. Functional assay revealed that none of the mutations within TKD showed autophosphorylation of CSF1R. The p.His362Arg variant located in the extracellular domain showed comparable autophosphorylation of CSF1R to the wild type, suggesting that this variant is not likely pathogenic. Conclusions: The detection of the CSF1R mutation outside of the region-encoding TKD may extend the genetic spectrum of ALSP with CSF1R mutations. Mutational analysis of all the coding exons of CSF1R should be considered for patients clinically suspected of having ALSP.",
keywords = "ALSP, CSF1R, HDLS, Haploinsufficiency, Leukoencephalopathy",
author = "Takeshi Miura and Naomi Mezaki and Takuya Konno and Akio Iwasaki and Naoyuki Hara and Masatomo Miura and Michitaka Funayama and Yuki Unai and Yuichi Tashiro and Kenji Okita and Takeshi Kihara and Nobuo Ito and Yoichi Kanatsuka and Jones, {David T.} and Norikazu Hara and Takanobu Ishiguro and Takayoshi Tokutake and Kensaku Kasuga and Hiroaki Nozaki and Dickson, {Dennis W.} and Osamu Onodera and Wszolek, {Zbigniew K.} and Takeshi Ikeuchi",
note = "Funding Information: We would like to thank the patients and their relatives for participating in this study and Ms. Reiko Kawai for her technical assistance. Dr. Konno is supported by JSPS Overseas Research Fellowships and the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch. Dr. Wszolek is partially supported by the NIH/NINDS P50 NS072187, NIH/NIA (primary) and NIH/NINDS (secondary) 1U01AG045390-01A1, Mayo Clinic Center for Regenerative Medicine, Mayo Clinic Neuroscience Focused Research Team (Cecilia and Dan Carmichael Family Foundation, and the James C. and Sarah K. Kennedy Fund for Neurodegenerative Disease Research at Mayo Clinic in Florida), the gift from The Sol Goldman Charitable Trust, and Donald G. and Jodi P. Heeringa. Dr. Ikeuchi is supported by JSPS KAKENHI Grant number JP16H01331 and 26117506, AMED under Grant number JP18kk0205009, and MHLW Grant number 18062640. The authors declare that they have no competing interests. Funding Information: Acknowledgements We would like to thank the patients and their relatives for participating in this study and Ms. Reiko Kawai for her technical assistance. Dr. Konno is supported by JSPS Overseas Research Fellowships and the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch. Dr. Wszolek is partially supported by the NIH/ NINDS P50 NS072187, NIH/NIA (primary) and NIH/NINDS (secondary) 1U01AG045390-01A1, Mayo Clinic Center for Regenerative Medicine, Mayo Clinic Neuroscience Focused Research Team (Cecilia and Dan Carmichael Family Foundation, and the James C. and Sarah K. Kennedy Fund for Neurodegenerative Disease Research at Mayo Clinic in Florida), the gift from The Sol Goldman Charitable Trust, and Donald G. and Jodi P. Heeringa. Dr. Ikeuchi is supported by JSPS KAKENHI Grant number JP16H01331 and 26117506, AMED under Grant number JP18kk0205009, and MHLW Grant number 18062640. Publisher Copyright: {\textcopyright} 2018, The Author(s).",
year = "2018",
month = oct,
day = "1",
doi = "10.1007/s00415-018-9017-2",
language = "English (US)",
volume = "265",
pages = "2415--2424",
journal = "Deutsche Zeitschrift fur Nervenheilkunde",
issn = "0340-5354",
publisher = "D. Steinkopff-Verlag",
number = "10",
}