How to Cite this Article: Mitsui J, Matsukawa T, Ishiura H, Higasa K, Yoshimura J, Saito TL, Ahsan B, Takahashi Y, Goto J, Iwata A, Niimi Y, Riku Y, Goto Y, Mano K, Yoshida M, Morishita S, Tsuji S. 2012. CSF1R Mutations Identified in Three Families With Autosomal Dominantly Inherited Leukoencephalopathy. Am J Med Genet Part B 159B:951–957.
Article first published online: 4 OCT 2012
Copyright © 2012 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
Volume 159B, Issue 8, pages 951–957, December 2012
How to Cite
Mitsui, J., Matsukawa, T., Ishiura, H., Higasa, K., Yoshimura, J., Saito, T. L., Ahsan, B., Takahashi, Y., Goto, J., Iwata, A., Niimi, Y., Riku, Y., Goto, Y., Mano, K., Yoshida, M., Morishita, S. and Tsuji, S. (2012), CSF1R mutations identified in three families with autosomal dominantly inherited leukoencephalopathy. Am. J. Med. Genet., 159B: 951–957. doi: 10.1002/ajmg.b.32100
Jun Mitsui and Takashi Matsukawa equally contributed to this work.
- Issue published online: 8 NOV 2012
- Article first published online: 4 OCT 2012
- Manuscript Accepted: 6 SEP 2012
- Manuscript Received: 24 APR 2012
- KAKENHI. Grant Numbers: 22129001, 22129002
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Ministry of Health, Welfare and Labour, Japan
- hereditary diffuse leukoencephalopathy with spheroids;
- exome sequencing;
- molecular diagnosis
Genetic and phenotypic heterogeneities are considerably high in adult-onset leukoencephalopathy, in which comprehensive mutational analyses of the candidate genes by conventional methods are too laborious. We applied exome sequencing to conduct a comprehensive mutational analysis of genes for autosomal dominant leukoencephalopathies. Genomic DNA samples from four patients of three families with autosomal dominantly inherited adult-onset leukodystrophy were subjected to exome sequencing. On the basis of the results, 21 patients with adult-onset sporadic leukodystrophy and one patient with pathologically proven HDLS were additionally screened for CSF1R mutations. Exome sequencing identified heterozygous CSF1R mutations (p.I794T and p.R777W) in two families. I794T has recently been reported as a causative mutation for hereditary diffuse leukoencephalopathy with spheroids (HDLS), and R777W is a novel mutation. Although mutational analysis of CSF1R in 21 sporadic cases revealed no mutations, another novel CSF1R mutation, p.C653Y, was identified in one patient with autopsy-proven HDSL. These variants were located in the PTK domain where the causative mutations cluster. Functional prediction of the mutant CSF1R as well as cross-species conservation of the affected amino acids supports the notion that these variants are pathogenic for HDLS. Exome sequencing is useful for a comprehensive mutational analysis of causative genes for hereditary leukoencephalopathies, and CSF1R should be considered a candidate gene for patients with autosomal dominant leukoencephalopathies. © 2012 Wiley Periodicals, Inc.