Topic
WDR45
About: WDR45 is a research topic. Over the lifetime, 70 publications have been published within this topic receiving 4659 citations. The topic is also known as: NBIA4 & NBIA5.
Papers
TL;DR: Patients with atypical disease who had PANK2 mutations were more likely to have prominent speech-related and psychiatric symptoms than patients with classic disease or mutation-negative patients with attypical disease.
Abstract: Background Hallervorden–Spatz syndrome is an autosomal recessive disorder characterized by dystonia, parkinsonism, and iron accumulation in the brain. Many patients with this disease have mutations in the gene encoding pantothenate kinase 2 (PANK2); these patients are said to have pantothenate kinase–associated neurodegeneration. In this study, we compared the clinical and radiographic features of patients with Hallervorden–Spatz syndrome with and without mutations in PANK2. Methods One hundred twenty-three patients from 98 families with a diagnosis of Hallervorden–Spatz syndrome were classified on the basis of clinical assessment as having classic disease (characterized by early onset with rapid progression) or atypical disease (later onset with slow progression). Their genomic DNA was sequenced for PANK2 mutations. Results All patients with classic Hallervorden–Spatz syndrome and one third of those with atypical disease had PANK2 mutations. Whereas almost all mutations in patients with atypical disease ...
774 citations
TL;DR: This work mapped a locus for infantile neuroaxonal dystrophy and neurodegeneration with brain iron accumulation to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome.
Abstract: Neurodegenerative disorders with high brain iron include Parkinson disease, Alzheimer disease and several childhood genetic disorders categorized as neuroaxonal dystrophies. We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome. This discovery implicates phospholipases in the pathogenesis of neurodegenerative disorders with iron dyshomeostasis.
547 citations
TL;DR: Although many recessive loci causing parkinsonism dystonia have been identified, these do not explain all cases of the disorder.
Abstract: Background
Although many recessive loci causing parkinsonism dystonia have been identified, these do not explain all cases of the disorder.
Methods
We used homozygosity mapping and mutational analysis in three individuals from two unrelated families who presented with adult-onset levodopa-responsive dystonia-parkinsonism, pyramidal signs and cognitive/psychiatric features, and cerebral and cerebellar atrophy on magnetic resonance imaging but absent iron in the basal ganglia.
Results
We identified areas of homozygosity on chromosome 22 and, subsequently, PLA2G6 mutations.
Interpretation
PLA2G6 mutations are associated with infantile neuroaxonal dystrophy and have been reported previously to cause early cerebellar signs, and the syndrome was classified as neurodegeneration with brain iron accumulation (type 2). Our cases have neither of these previously pathognomic features. Thus, mutations in PLA2G6 should additionally be considered in patients with adult-onset dystonia-parkinsonism even with absent iron on brain imaging. Ann Neurol 2008
508 citations
TL;DR: Findings provide direct evidence that an autophagy defect is indeed associated with a neurodegenerative disorder in humans.
Abstract: Hirotomo Saitsu, Noboru Mizushima, Naomichi Matsumoto and colleagues report the identification of de novo mutations in WDR45 that cause static encephalopathy of childhood with neurodegeneration in adulthood. WDR45 encodes a homolog of the yeast autophagy protein Atg18.
459 citations
Technische Universität München1, Oregon Health & Science University2, Great Ormond Street Hospital3, University College London4, University of Arkansas for Medical Sciences5, Carlo Besta Neurological Institute6, McMaster University7, Icahn School of Medicine at Mount Sinai8, Albany Medical College9, Maastricht University Medical Centre10, Necker-Enfants Malades Hospital11
TL;DR: De novo mutations in WDR45, a gene located at Xp11.23 and encoding a beta-propeller scaffold protein with a putative role in autophagy, cause a distinctive NBIA phenotype, and it is suggested that this clinically recognizable disorder be named accordingly as beta- Propeller protein-associated neurodegeneration.
Abstract: Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic disorders characterized by abnormal iron deposition in the basal ganglia. We report that de novo mutations in WDR45, a gene located at Xp11.23 and encoding a beta-propeller scaffold protein with a putative role in autophagy, cause a distinctive NBIA phenotype. The clinical features include early-onset global developmental delay and further neurological deterioration (parkinsonism, dystonia, and dementia developing by early adulthood). Brain MRI revealed evidence of iron deposition in the substantia nigra and globus pallidus. Males and females are phenotypically similar, an observation that might be explained by somatic mosaicism in surviving males and germline or somatic mutations in females, as well as skewing of X chromosome inactivation. This clinically recognizable disorder is among the more common forms of NBIA, and we suggest that it be named accordingly as beta-propeller protein-associated neurodegeneration.
366 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2021 | 4 |
| 2020 | 6 |
| 2019 | 5 |
| 2018 | 5 |
| 2017 | 8 |
| 2016 | 9 |