WDR45 Mutation in Atypical Rett Syndrome with Brain Iron Accumulation.
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ABSTRACT:
SUBMITTER: Crisp SJ
PROVIDER: S-EPMC6353382 | biostudies-literature | 2015 Mar
REPOSITORIES: biostudies-literature
Publications
<i>WDR45</i> Mutation in Atypical Rett Syndrome with Brain Iron Accumulation.
Crisp Sarah J SJ Meyer Esther E Gregory Allison A Archer Hayley H Hayflick Susan S Kurian Manju A MA de Silva Rajith R
Movement disorders clinical practice 20150224 1
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Project description:Neurodegeneration with brain iron accumulation (NBIA) is a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by the abnormal accumulation of brain iron and the progressive degeneration of the nervous system. One of the recently identified subtypes of NBIA is β-propeller protein-associated neurodegeneration (BPAN). BPAN is caused by de novo mutations in the WDR45/WIPI4 (WD repeat domain 45) gene. WDR45 is one of the four mammalian homologs of yeast Atg18, a regulator of autophagy. WDR45 deficiency in BPAN patients and animal models may result in defects in autophagic flux. However, how WDR45 deficiency leads to brain iron overload remains unclear. To elucidate the role of WDR45, we generated a WDR45-knockout (KO) SH-SY5Y neuroblastoma cell line using CRISPR-Cas9-mediated genome editing. Using these cells, we demonstrated that the non-TF (transferrin)-bound iron pathway dominantly mediated the accumulation of iron. Moreover, the loss of WDR45 led to defects in ferritinophagy, a form of autophagy that degrades the iron storage protein ferritin. We showed that impaired ferritinophagy contributes to iron accumulation in WDR45-KO cells. Iron accumulation was also detected in the mitochondria, which was accompanied by impaired mitochondrial respiration, elevated reactive oxygen species, and increased cell death. Thus, our study links WDR45 to specific iron acquisition pathways and ferritinophagy. Cover Image for this issue: https://doi.org/10.1111/jnc.15388.
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Project description:BACKGROUND:Some typical and atypical Rett syndrome patients lack known genetic mutations. Mutations in the P/Q type calcium channel CACNA1A have been implicated in epileptic encephalopathy, familial hemiplegic migraine, episodic ataxia 2, and spinocerebellar ataxia 6, but not Rett syndrome. Patient Description: The authors describe a female patient with developmental regression and a de novo, likely pathogenic mutation in CACNA1A who meets 3 of 4 main criteria (stereotypic hand movements, loss of purposeful hand movements, gait disturbance), and 6 of 11 supportive criteria (impaired sleep, abnormal tone, vasomotor disturbance, scoliosis, growth retardation, and screaming spells) for atypical Rett syndrome. Furthermore, she resembles the early seizure variant of Rett syndrome. Previously, 3 children with similar CACNA1A mutations have been reported, but a Rett syndrome phenotype has not been described. CONCLUSION:CACNA1A mutations should be considered in children presenting with an atypical Rett syndrome phenotype, specifically, the early seizure variant.
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Project description:Iron overload in the brain, defined as excess stores of iron, is known to be associated with neurological disorders. In neurodegeneration accompanied by brain iron accumulation, we reported a specific point mutation, c.974-1G>A in WD Repeat Domain 45 (WDR45), showing iron accumulation in the brain, and autophagy defects in the fibroblasts. In this study, we investigated whether fibroblasts with mutated WDR45 accumulated iron, and other effects on cellular organelles. We first identified the main location of iron accumulation in the mutant fibroblasts and then investigated the effects of this accumulation on cellular organelles, including lipid droplets, mitochondria and lysosomes. Ultrastructure analysis using transmission electron microscopy (TEM) and confocal microscopy showed structural changes in the organelles. Increased numbers of lipid droplets, fragmented mitochondria and increased numbers of lysosomal vesicles with functional disorder due to WDR45 deficiency were observed. Based on correlative light and electron microscopy (CLEM) findings, most of the iron accumulation was noted in the lysosomal vesicles. These changes were associated with defects in autophagy and defective protein and organelle turnover. Gene expression profiling analysis also showed remarkable changes in lipid metabolism, mitochondrial function, and autophagy-related genes. These data suggested that functional and structural changes resulted in impaired lipid metabolism, mitochondrial disorder, and unbalanced autophagy fluxes, caused by iron overload.
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Project description:Iron overload in the brain, defined as excess stores of iron, is known to be related to neurological disorder. Among neurodegeneration with brain iron accumulation, we reported a specific point mutation, 977-1G>A in WDR45, showing iron accumulation in the brain, and autophagy defects in the fibroblasts. In this study, we investigated whether fibroblasts with mutated WDR45 accumulated iron, and other effects on cellular organelles. We first identified the main location of iron accumulation in the mutant fibroblasts and then investigated the effects of this accumulation on other organelles, including lipid droplets, mitochondria, and lysosomes. Ultrastructure analysis using transmission electron microscopy (TEM) and confocal microscopy showed structural changes in the organelles. Increased numbers of lipid droplets, fragmented mitochondria, and increased lysosomal vesicles with functional disorder due to WDR45 deficiency were observed. The majority of iron accumulation occurred in the lysosomal vesicles, according to correlative light and electron microscopy (CLEM). These changes were related to defects in autophagy and defective protein and organelle turnover. Gene expression profiling analysis also showed significant changes in lipid metabolism, mitochondrial function, and autophagy-related genes. Those data suggested that functional and structural changes caused impaired lipid metabolism, mitochondrial disorder, and unbalanced autophagy fluxes, due to iron overload.
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Project description:Rett syndrome (RTT) is a rare congenital disorder which in most cases (95%) is caused by methyl-CpG binding protein 2 (MECP2) mutations. RTT is characterized by regression in global development, epilepsy, autistic features, acquired microcephaly, habitual hand clapping, loss of purposeful hand skills, and autonomic dysfunctions. Although the literature has demonstrated decreased volumes of the cerebrum, cerebellum, and the caudate nucleus in RTT patients, surface-based brain morphology including cortical thickness and cortical gyrification analyses are lacking in RTT. We present quantitative surface- and voxel-based morphological measurements in young children with RTT and Rett-like syndrome (RTT-l) with MECP2 mutations. The 8 structural T1-weighted MR images were obtained from 7 female patients with MECP2 mutations (3 classic RTT, 2 variant RTT, and 2 RTT-l) (mean age 5.2 [standard deviation 3.3] years old). Our analyses demonstrated decreased total volumes of the cerebellum in RTT/RTT-l compared to gender- and age-matched controls (t (22)=-2.93, p?=?.008, Cohen's d?=?1.27). In contrast, global cerebral cortical surface areas, global/regional cortical thicknesses, the degree of global gyrification, and global/regional gray and white matter volumes were not statistically significantly different between the two groups. Our findings, as well as literature findings, suggest that early brain abnormalities associated with RTT/RTT-l (with MECP2 mutations) can be detected as regionally decreased cerebellar volumes. Decreased cerebellar volume may be helpful for understanding the etiology of RTT/RTT-l.
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Project description:Rett syndrome (RTT) was first described in 1966. Its biological and genetic foundations were not clear until recently when Amir et al reported that mutations in the MECP2 gene were detected in around 50% of RTT patients. In this study, we have screened the MECP2 gene for mutations in our RTT material, including nine familial cases (19 Rett girls) and 59 sporadic cases. A total of 27 sporadic RTT patients were found to have mutations in the MECP2 gene, but no mutations were identified in our RTT families. In order to address the possibility of further X chromosomal or autosomal genetic factors in RTT, we evaluated six candidate genes for RTT selected on clinical, pathological, and genetic grounds: UBE1 (human ubiquitin activating enzyme E1, located in chromosome Xp11.23), UBE2I (ubiquitin conjugating enzyme E2I, homologous to yeast UBC9, chromosome 16p13.3), GdX (ubiquitin-like protein, chromosome Xq28), SOX3 (SRY related HMG box gene 3, chromosome Xq26-q27), GABRA3 (gamma-aminobutyric acid type A receptor alpha3 subunit, chromosome Xq28), and CDR2 (cerebellar degeneration related autoantigen 2, chromosome 16p12-p13.1). No mutations were detected in the coding regions of these six genes in 10 affected subjects and, therefore, alterations in the amino acid sequences of the encoded proteins can be excluded as having a causative role in RTT. Furthermore, gene expression of MECP2, GdX, GABRA3, and L1CAM (L1 cell adhesion molecule) was also investigated by in situ hybridisation. No gross differences were observed in neurones of several brain regions between normal controls and Rett patients.
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Project description:Mutations in Methyl-CpG binding protein 2 (MECP2) have been identified as the disease-causing mutations in Rett Syndrome (RTT). However, no mutation in the AT-hook 1 domain of MECP2 has been reported in RTT yet. The function of AT-hook 1 domain of MECP2 has not been described either.The clinical and radiological features of a girl with progressive hyperactivity and loss of acquired linguistic and motor functions were presented. Next generation sequencing was used to screen the causative gene. Effect of the mutant protein on histone 3 methylation was assessed in vitro experiment.The patient was diagnosed with an atypical RTT at the age of nine. Magnetic resonance imaging revealed a loss of whole-brain volume and abnormal myelination. Genetic analysis identified a de novo novel missense mutation of MECP2 (NM_004992, c.570G->A, p.Arg190His). This mutation is located in the AT-hook 1 domain of MeCP2 protein. Overexpression of the mutant MeCP2 in cultured neuroblastoma cells SH-SY5Y revealed increased level of dimethylated histone 3 lysine 9, a transcriptional repressor marker.A novel missense mutation in AT-hook 1 domain of MeCP2 was identified in a patient with atypical RTT. Clinical data and in vitro experiment result imply that R190H mutation in AT-hook1 may cause dysfunction of MeCP2 and be a pathogenic variant.
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Project description:Transcriptome analysis of postmortem brain samples frrom frontal and temporal cortex of Rett Syndrome cases and matched controls. These data identify genes differentially expressed in postmortem brain tissue from Rett Syndrome cases. Total RNA was extracted from 100mg of postmortem brain tissue.
2015-11-24 | E-GEOD-75303 | biostudies-arrayexpress
Project description:Transcriptome analysis of postmortem brain samples frrom frontal and temporal cortex of Rett Syndrome cases and matched controls. These data identify genes differentially expressed in postmortem brain tissue from Rett Syndrome cases.
2015-11-24 | GSE75303 | GEO