Dataset Information

Duplication and deletion upstream of LMNB1 in autosomal dominant adult-onset leukodystrophy.

ABSTRACT: Objective:To characterize the genetic and clinical features of patients with autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) carrying duplication and deletion upstream of lamin B1 (LMNB1). Methods:Ninety-three patients with adult-onset leukoencephalopathy of unknown etiology were genetically analyzed for copy numbers of LMNB1 and its upstream genes. We examined LMNB1 expression by reverse transcription-qPCR using total RNA extracted from peripheral leukocytes. Clinical and MRI features of the patients with ADLD were retrospectively analyzed. Results:We identified 4 patients from 3 families with LMNB1 duplication. The duplicated genomic regions were different from those previously reported. The mRNA expression level of LMNB1 in patients with duplication was significantly increased. The clinical features of our patients with LMNB1 duplication were similar to those reported previously, except for the high frequency of cognitive impairment in our patients. We found 2 patients from 1 family carrying a 249-kb genomic deletion upstream of LMNB1. Patients with the deletion exhibited relatively earlier onset, more prominent cognitive impairment, and fewer autonomic symptoms than patients with duplication. The presence of cerebellar symptoms and lesions may be characteristic in our patients with the deletion compared with the previously reported family with the deletion. Magnetic resonance images of patients with the deletion exhibited a widespread distribution of white matter lesions including the anterior temporal region. Conclusions:We identified 4 Japanese families with ADLD carrying duplication or deletion upstream of LMNB1. There are differences in clinical and MRI features between the patients with the duplication and those with the deletion upstream of LMNB1.

SUBMITTER: Mezaki N

PROVIDER: S-EPMC6340331 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Duplication and deletion upstream of <i>LMNB1</i> in autosomal dominant adult-onset leukodystrophy.

Mezaki Naomi N Miura Takeshi T Ogaki Kotaro K Eriguchi Makoto M Mizuno Yuri Y Komatsu Kenichi K Yamazaki Hiroki H Suetsugi Natsuki N Kawajiri Sumihiro S Yamasaki Ryo R Ishiguro Takanobu T Konno Takuya T Nozaki Hiroaki H Kasuga Kensaku K Okuma Yasuyuki Y Kira Jun-Ichi JI Hara Hideo H Onodera Osamu O Ikeuchi Takeshi T

Neurology. Genetics 20181207 6

<h4>Objective</h4>To characterize the genetic and clinical features of patients with autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) carrying duplication and deletion upstream of lamin B1 (<i>LMNB1</i>).<h4>Methods</h4>Ninety-three patients with adult-onset leukoencephalopathy of unknown etiology were genetically analyzed for copy numbers of <i>LMNB1</i> and its upstream genes. We examined <i>LMNB1</i> expression by reverse transcription-qPCR using total RNA extracted from per ...[more]

PMID: 30697589

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Project description:Tissue-resident macrophages of the brain, including microglia, are implicated in the pathogenesis of various CNS disorders and are possible therapeutic targets by their chemical depletion or replenishment by hematopoietic stem cell therapy. Nevertheless, a comprehensive understanding of microglial function and the consequences of microglial depletion in the human brain is lacking. In human disease, heterozygous variants in CSF1R, encoding the Colony-stimulating factor 1 receptor, can lead to adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) possibly caused by microglial depletion. Here, we investigate the effects of ALSP-causing CSF1R variants on microglia and explore the consequences of microglial depletion in the brain. In intermediate- and late-stage ALSP post-mortem brain, we establish that there is an overall loss of homeostatic microglia and that this is predominantly seen in the white matter. By introducing ALSP-causing missense variants into the zebrafish genomic csf1ra locus, we show that these variants act dominant negatively on the number of microglia in vertebrate brain development. Transcriptomics and proteomics on relatively spared ALSP brain tissue validated a downregulation of microglia-associated genes and revealed elevated astrocytic proteins, possibly suggesting involvement of astrocytes in early pathogenesis. Indeed, neuropathological analysis and in vivo imaging of csf1r zebrafish models showed an astrocytic phenotype associated with enhanced, possibly compensatory, endocytosis. Together, our findings indicate that microglial depletion in zebrafish and human disease, likely as a consequence of dominant-acting pathogenic CSF1R variants, correlates with altered astrocytes. These findings underscore the unique opportunity CSF1R variants provide to gain insight into the roles of microglia in the human brain, and the need to further investigate how microglia, astrocytes, and their interactions contribute to white matter homeostasis.

Dataset Information

Duplication and deletion upstream of LMNB1 in autosomal dominant adult-onset leukodystrophy.

Publications

Duplication and deletion upstream of <i>LMNB1</i> in autosomal dominant adult-onset leukodystrophy.

Similar Datasets

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