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CSF1R mutations in hereditary diffuse leukoencephalopathy with spheroids are loss of function.

ABSTRACT: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) in humans is a rare autosomal dominant disease characterized by giant neuroaxonal swellings (spheroids) within the CNS white matter. Symptoms are variable and can include personality and behavioural changes. Patients with this disease have mutations in the protein kinase domain of the colony-stimulating factor 1 receptor (CSF1R) which is a tyrosine kinase receptor essential for microglia development. We investigated the effects of these mutations on Csf1r signalling using a factor dependent cell line. Corresponding mutant forms of murine Csf1r were expressed on the cell surface at normal levels, and bound CSF1, but were not able to sustain cell proliferation. Since Csf1r signaling requires receptor dimerization initiated by CSF1 binding, the data suggest a mechanism for phenotypic dominance of the mutant allele in HDLS.

SUBMITTER: Pridans C

PROVIDER: S-EPMC3804858 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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CSF1R mutations in hereditary diffuse leukoencephalopathy with spheroids are loss of function.

Pridans Clare C Sauter Kristin A KA Baer Kristin K Kissel Holger H Hume David A DA

Scientific reports 20131022

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) in humans is a rare autosomal dominant disease characterized by giant neuroaxonal swellings (spheroids) within the CNS white matter. Symptoms are variable and can include personality and behavioural changes. Patients with this disease have mutations in the protein kinase domain of the colony-stimulating factor 1 receptor (CSF1R) which is a tyrosine kinase receptor essential for microglia development. We investigated the effects of thes ...[more]

PMID: 24145216

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Parkinsonian features in hereditary diffuse leukoencephalopathy with spheroids (HDLS) and CSF1R mutations.

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Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids.

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Functional characterization of a novel CSF1R mutation causing hereditary diffuse leukoencephalopathy with spheroids.

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Suspected Perinatal Depression Revealed to be Hereditary Diffuse Leukoencephalopathy with Spheroids.

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Hereditary diffuse leukoencephalopathy with spheroids with phenotype of primary progressive multiple sclerosis.

Project description:Background and purposeHereditary diffuse leukoencephalopathy with spheroids (HDLS) is a devastating, hereditary white matter (WM) disorder with heterogeneous neuropsychiatric features. Colony stimulating factor 1 receptor (CSF1R) mutations were looked for in primary progressive multiple sclerosis (PPMS) patients and the clinical features of a family with a novel CSF1R mutation are reported.MethodsCSF1R exons 12-22 in a cohort of 220 PPMS patients from the Swedish and Norwegian national multiple sclerosis registries were sequenced.ResultsOne patient had a novel mutation, c.2562T>A; p.Asn854Lys, in the CSF1R gene. Her symptoms started at the age of 29 years with insidious onset of pyramidal weakness in the left leg. The cerebrospinal fluid examination showed four intrathecal immunoglobulin G bands. A magnetic resonance imaging scan performed 4 years after symptom onset demonstrated patchy deep WM lesions. She was diagnosed as having PPMS and treated with intramuscular interferon beta 1a. Due to slow disease progression, the development of memory decline and cerebellar signs, she was given subcutaneous interferon beta 1a without any benefit. The updated pedigree indicated that five siblings also had the CSF1R gene mutation; one was diagnosed with PPMS. Six more distant relatives also had a neurological disorder; four were clinically diagnosed with PPMS.ConclusionsOur study indicates that a chronic course of HDLS may mimic PPMS. Genetic testing for CSF1R gene mutations in PPMS cases with a positive family history of neurological disorders may establish the diagnosis of HDLS.

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Enlarging the nosological spectrum of hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS).

Project description:Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is an autosomal dominant disease clinically characterized by cognitive decline, personality changes, motor impairment, parkinsonism and seizures. Recently, mutations in the colony-stimulating factor-1 receptor (CSF1R) gene have been shown to be associated with HDLS. We report clinical, neuropathological and molecular genetic findings of patients from a new family with a mutation in the CSF1R gene. Disease onset was earlier and disease progression was more rapid compared with previously reported patients. Psychiatric symptoms including personality changes, alcohol abuse and severe depression were the first symptoms in male patients. In the index, female patient, the initial symptom was cognitive decline. Magnetic resonance imaging (MRI) showed bilateral, confluent white matter lesions in the cerebrum. Stereotactic biopsy revealed loss of myelin and microglial activation as well as macrophage infiltration of the parenchyma. Numerous axonal swellings and spheroids were present. Ultrastructural analysis revealed pigment-containing macrophages. Axonal swellings were detected by electron microscopy not only in the central nervous system (CNS) but also in skin nerves. We identified a heterozygous mutation (c.2330G>A, p.R777Q) in the CSF1R gene. Through this report, we aim to enlarge the nosological spectrum of HDLS, providing new clinical descriptions as well as novel neuropathological findings from the peripheral nervous system.

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A proposed synergistic effect of <i>CSF1R</i> and <i>NMUR2</i> variants contributes to binge eating in hereditary diffuse leukoencephalopathy with spheroids.

Project description:BackgroundThe genetic mechanisms of binge eating (BE) as a disease identity remain obscure. BE is usually viewed as a part of the behavioral variant of frontotemporal dementia (bvFTD) features. We encountered a family with hereditary diffuse leukoencephalopathy with spheroids (HDLS) that manifested uniformly with binge-eating-onset dementia. The genetic factors associated with the rare phenotype were investigated.MethodsThe detailed phenotypes of the patients were described. We performed whole-exome sequencing (WES) of family members and repeat-primed PCR to analyze the patients' expansion size of C9orf72, a well-established gene causing FTD. The WES results of additional HDLS patients without BE manifestations were also investigated.ResultsAll affected individuals had a BE-dementia-epilepsy pattern of disease progression. A recurrent disease-causing mutation in CSF1R established the diagnosis of HDLS in the family. No abnormalities in the expansion size of C9orf72 were detected. The concurrence of a recurrent CSF1R mutation and a rare variant in NMUR2, a gene functionally related to BE, was revealed in the affected family members. No potentially pathogenic variants in other known BE-associated genes were identified. Both the NMUR2 variant and the CSF1R mutation cosegregated with the BE-dementia-epilepsy phenotype in the family. In three additional HDLS patients without BE, no pathogenic variants in NMUR2 were detected.ConclusionsWe propose that synergistic genetic effects of NMUR2 and CSF1R variants may exist and contribute to the development of the BE phenotype in HDLS. NMUR2 is one of the potential susceptible genes in BE and may contribute in a background of a disrupted structural neuronetwork. Further studies in other BE-related disorders are required.

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A novel A781V mutation in the CSF1R gene causes hereditary diffuse leucoencephalopathy with axonal spheroids.

Project description:We report a family with a novel CSF1R mutation causing hereditary diffuse leucoencephalopathy with axonal spheroids. Family members presented with neuropsychiatric and behavioural symptoms, with subsequent development of motor symptoms and gait disturbance. MRI brain showed extensive white matter change with a frontal predominance and associated atrophy in two members of the family. Genetic testing revealed a novel mutation c.2342C>T (p.A781V) in the CSF1R gene in two brothers of the family. This report highlights the difficulties in diagnosing HDLS and discusses the indications for testing for mutations in the CSF1R gene.

| S-EPMC3750216 | biostudies-literature

An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids.

Project description:Swedish type Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS-S) is a severe adult-onset leukoencephalopathy with the histopathological hallmark of neuraxonal degeneration with spheroids, described in a large family with a dominant inheritance pattern. The initial stage of the disease is dominated by frontal lobe symptoms that develop into a rapidly advancing encephalopathy with pyramidal, deep sensory, extrapyramidal and optic tract symptoms. Median survival is less than 10?years. Recently, pathogenic mutations in CSF1R were reported in a clinically and histologically similar leukoencephalopathy segregating in several families. Still, the cause of HDLS-S remained elusive since its initial description in 1984, with no CSF1R mutations identified in the family. Here we update the original findings associated with HDLS-S after a systematic and recent assessment of several family members. We also report the results from exome sequencing analyses indicating the p.Cys152Phe variant in the alanyl tRNA synthetase (AARS) gene as the probable cause of this disease. The variant affects an amino acid located in the aminoacylation domain of the protein and does not cause differences in splicing or expression in the brain. Brain pathology in one case after 10?years of disease duration showed the end stage of the disease to be characterized by widespread liquefaction of the white matter leaving only some macrophages and glial cells behind the centrifugally progressing front. These results point to AARS as a candidate gene for rapidly progressing adult-onset CSF1R-negative leukoencephalopathies.

| S-EPMC6880494 | biostudies-literature

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