A novel<i>RAB39B</i>gene mutation in X-linked juvenile parkinsonism with basal ganglia calcification

Shi, Changhe; Zhang, Shuyu; Yang, Zhihua; Yang, Jing; Shang, Donghao; Mao, Chengyuan; Liu, Hao; Hou, Haiman; Shi, Mengmeng; Wu, Jun; Xu, Yuming

doi:10.1002/mds.26828

Cited by 41 publications

(51 citation statements)

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“…Recently, our team also identified a novel mutation of Rab39b (c.536 dup A) in a family, of which the patients displayed juvenile parkinsonism and mental retardation syndromes. Moreover, the brain magnetic resonance imaging (MRI) and computed tomography (CT) scans of both patients showed calcification in the basal ganglia, which was never reported in the previous cases (Shi et al, 2016). According to the latest study, the complex formed by C9ORF72, WDR41 and SMCR8 worked as a GEF for Rab39b as well as Rab8a, which suggested that Rab39b might be involved in the autophagy regulation (Sellier et al, 2016).…”

Section: The Interactions Between Rabs and Different Pd-related Genessupporting

confidence: 49%

“…Parkinson’s disease (PD) is the second most prevalent chronic neurodegenerative disorder of aging, clinically characterized by motor symptoms including resting tremor, muscle rigidity, bradykinesia, postural instability and various non-motor symptoms (Shi et al, 2016). The most evident pathological features are the progressive degeneration of dopaminergic neurons and axonal projections in the substantia nigra and the wide spreading of eosinophilic Lewy bodies whose cardinal component is α-synuclein detected in some surviving neurons (Goedert et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, a series of recent studies have revealed that certain Rabs are involved in the modulation of α-synuclein. Impairment of these proteins have been reported to be one of the rare causes for inherited early onset PD (Wilson et al, 2014; Lesage et al, 2015; Mata et al, 2015; Shi et al, 2016). These new findings provide a novel insight into the molecular pathogenesis of PD.…”

Section: Introductionmentioning

confidence: 99%

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Rab GTPases: The Key Players in the Molecular Pathway of Parkinson’s Disease

Shi

2017

Front. Cell. Neurosci.

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Parkinson's disease (PD) is a progressive movement disorder with multiple non-motor symptoms. Although family genetic mutations only account for a small proportion of the cases, these mutations have provided several lines of evidence for the pathogenesis of PD, such as mitochondrial dysfunction, protein misfolding and aggregation, and the impaired autophagy-lysosome system. Recently, vesicle trafficking defect has emerged as a potential pathogenesis underlying this disease. Rab GTPases, serving as the core regulators of cellular membrane dynamics, may play an important role in the molecular pathway of PD through the complex interplay with numerous factors and PD-related genes. This might shed new light on the potential therapeutic strategies. In this review, we emphasize the important role of Rab GTPases in vesicle trafficking and summarize the interactions between Rab GTPases and different PD-related genes.

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Section: The Interactions Between Rabs and Different Pd-related Genessupporting

confidence: 49%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rab GTPases: The Key Players in the Molecular Pathway of Parkinson’s Disease

Shi

2017

Front. Cell. Neurosci.

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“…Significant associations at different loci—Discs large homolog of 2 ( DLG2 ), Sipa1-like protein ( SIPA1L2 ), Serine/Theonine kinase 39 ( STK39 ), Vacuolar protein sorting 13 homolog C ( VPS13C ), Ric-like protein without CAAX motif 2 ( RIT2 ), BST1 , PARK16 —have been found in Asians vs. Europeans, together with allelic heterogeneity at LRRK2 and at six other loci including MAPT and GBA-SYT11 [50]. Some other candidate genes have been recently reported to be associated with PD in different cohorts (i.e., RAD51B [39], DYRK1A [53], CHCHD2 [54], VPS35 [55], RAB39B [56], TMEM230 [57]).…”

Section: Pathogenic Mechanismsmentioning

confidence: 99%

Parkinson’s Disease: From Pathogenesis to Pharmacogenomics

Cacabelos

2017

IJMS

431

300

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Parkinson’s disease (PD) is the second most important age-related neurodegenerative disorder in developed societies, after Alzheimer’s disease, with a prevalence ranging from 41 per 100,000 in the fourth decade of life to over 1900 per 100,000 in people over 80 years of age. As a movement disorder, the PD phenotype is characterized by rigidity, resting tremor, and bradykinesia. Parkinson’s disease -related neurodegeneration is likely to occur several decades before the onset of the motor symptoms. Potential risk factors include environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage, and genomic defects. Parkinson’s disease neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta, with widespread involvement of other central nervous system (CNS) structures and peripheral tissues. Pathogenic mechanisms associated with genomic, epigenetic and environmental factors lead to conformational changes and deposits of key proteins due to abnormalities in the ubiquitin–proteasome system together with dysregulation of mitochondrial function and oxidative stress. Conventional pharmacological treatments for PD are dopamine precursors (levodopa, l-DOPA, l-3,4 dihidroxifenilalanina), and other symptomatic treatments including dopamine agonists (amantadine, apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine), monoamine oxidase (MAO) inhibitors (selegiline, rasagiline), and catechol-O-methyltransferase (COMT) inhibitors (entacapone, tolcapone). The chronic administration of antiparkinsonian drugs currently induces the “wearing-off phenomenon”, with additional psychomotor and autonomic complications. In order to minimize these clinical complications, novel compounds have been developed. Novel drugs and bioproducts for the treatment of PD should address dopaminergic neuroprotection to reduce premature neurodegeneration in addition to enhancing dopaminergic neurotransmission. Since biochemical changes and therapeutic outcomes are highly dependent upon the genomic profiles of PD patients, personalized treatments should rely on pharmacogenetic procedures to optimize therapeutics.

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“…RAB39B c.536dupA (p.E179fsX48) was identified in a small Chinese family with two male patients who had learning difficulty from childhood and mild intellectual disability [72]. Both developed tremor and rigidity at age 10 and 12 years, progressing to moderate or severe PD by ages 20 and 58 years.…”

Section: New Genes For Recessive and X-linked Pd Or Parkinsonismmentioning

confidence: 99%

New Genes Causing Hereditary Parkinson’s Disease or Parkinsonism

Puschmann

2017

Curr Neurol Neurosci Rep

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Purpose of ReviewThis article reviews genes where putative or confirmed pathogenic mutations causing Parkinson’s disease or Parkinsonism have been identified since 2012, and summarizes the clinical and pathological picture of the associated disease subtypes.Recent FindingsNewly reported genes for dominant Parkinson’s disease are DNAJC13, CHCHD2, and TMEM230. However, the evidence for a disease-causing role is not conclusive, and further genetic and functional studies are warranted. RIC3 mutations have been reported from one family but not yet encountered in other patients. New genes for autosomal recessive disease include SYNJ1, DNAJC6, VPS13C, and PTRHD1. Deletions of a region on chromosome 22 (22q11.2del) are also associated with early-onset PD, but the mode of inheritance and the underlying causative gene remain unclear. PODXL mutations were reported in autosomal recessive PD, but their roles remain to be confirmed. Mutations in RAB39B cause an X-linked Parkinsonian disorder. SummaryMutations in the new dominant PD genes have generally been found in medium- to late-onset Parkinson’s disease. Many mutations in the new recessive and X-chromosomal genes cause severe atypical juvenile Parkinsonism, but less devastating mutations in these genes may cause PD.

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A novelRAB39Bgene mutation in X-linked juvenile parkinsonism with basal ganglia calcification

Abstract: X-linked juvenile parkinsonism could be caused by a RAB39B mutation, and basal ganglia calcification may be a novel clinical feature of RAB39B-related parkinsonism. © 2016 International Parkinson and Movement Disorder Society.

Cited by 41 publications

References 28 publications

Rab GTPases: The Key Players in the Molecular Pathway of Parkinson’s Disease

Rab GTPases: The Key Players in the Molecular Pathway of Parkinson’s Disease

Parkinson’s Disease: From Pathogenesis to Pharmacogenomics

New Genes Causing Hereditary Parkinson’s Disease or Parkinsonism

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