Novel compound heterozygous FBXO7 mutations in a family with early onset Parkinson's disease

Lorenzo‐Betancor, Oswaldo; Lin, Yihan; Samii, Ali; Jayadev, Suman; Kim, Hojoong M.; Longfellow, Katelan; Distad, B. Jane; Yearout, Dora; Mata, Ignacio; Zabetian, Cyrus P.

doi:10.1016/j.parkreldis.2020.09.035

Cited by 10 publications

(4 citation statements)

References 13 publications

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“…Pathways include immune system [83], adaptive immune system [84], neutrophil degranulation [85], cytokine signaling in immune system [86] and GPCR ligand binding [87] were responsible for progression of COVID-19 infection. A previous study demonstrated that the expression levels of AHSP (alpha hemoglobin stabilizing protein) [88], IL7R [89], FBXO7 [90], KLRB1 [91], PIP4K2A [92], NFE2 [93], CCR2 [94], CLEC12A [95], NLRP12 [96], PECAM1 [97], TRIM10 [98], ICAM3 [99], EEF1A1 [100], CCR4 [101], PTPRC (protein tyrosine phosphatase receptor type C) [102], CX3CR1 [103], TSPAN32 [104], EOMES (eomesodermin) [105], ATM (ATM serine/threonine kinase) [106], CD28 [107], LRRK2 [108], CCL5 [109], CD33 [110], FCRL3 [111], CCR3 [112], FGL2 [113], GZMA (granzyme A) [114], PICALM (phosphatidylinositol binding clathrin assembly protein) [115], ALOX5 [116], MME (membrane metalloendopeptidase) [117], VIM (vimentin) [118], CD93 [119], GCA (grancalcin) [120], CD226 [121], CD1D [122], TNFSF4 [123], LEF1 [124], TLR4 [125], CCR7 [126], DPP4 [127], NLRC4 [128], ITGB3 [129], RASGRP1 [130], TLR2 [131], DOCK2 [132], CSF1R [133], PRKCB (protein kinase C beta) [134], CAMK4 [135], CXCL5 [136], CD36 [137], P2RY12 [138], LILRB2 [139], CD5 [140], SLC25A37 [141], ADIPOR1 [142], PECAM1 [143], RGS10 [144], RGS18 [145], ANK1 [146], RNF182 [147], NPRL3 [148], NINJ2 [149], KCNA3 [150], ABCG2 [151], MS4A6A [152], WDR45 [153], RAB39B...…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of next-generation sequencing data in COVID-19 and its secondary complications

Vastrad¹,

Vastrad²

2022

Preprint

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The ongoing pandemic of coronavirus disease 2019 (COVID-19) has made a serious public health threat globally. To discover key molecular changes in COVID-19 and its secondary complications, we analyzed next-generation sequencing (NGS) data of COVID-19. NGS data (GSE163151) was screened and downloaded from the Gene Expression Omnibus database (GEO). Differentially expressed genes (DEGs) were identified in the present study, using DESeq2 package in R programming software. Gene ontology (GO) and pathway enrichment analysis were performed, and the protein-protein interaction (PPI) network, module analysis, miRNA-hub gene regulatory network and TF-hub gene regulatory network were established. Subsequently, receiver operating characteristic curve (ROC) analysis was used to validate the diagonostics valuesof the hub genes. Firstly, 954 DEGs (477 up regulated and 477 down regulated) were identified from the four NGS dataset. GO enrichment analysis revealed enrichment of DEGs in genes related to the immune system process and multicellular organismal process, and REACTOME pathway enrichment analysis showed enrichment of DEGs in the immune system and formation of the cornified envelope. Hub genes were identified from the PPI network, module analysis, miRNA-hub gene regulatory network and TF-hub gene regulatory network. Furthermore, the ROC analysis indicate that COVID-19 and its secondary complications with following hub genes, namely, RPL10, FYN, FLNA, EEF1A1, UBA52, BMI1, ACTN2, CRMP1, TRIM42 and PTCH1, had good diagnostics values. This study identified several genes associated with COVID-19 and its secondary complications, which improves our knowledge of the disease mechanism.

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Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of next-generation sequencing data in COVID-19 and its secondary complications

Vastrad¹,

Vastrad²

2022

Preprint

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“…Alternative treatment with dopamine receptor agonist triggered psychiatric side effects including agitation, repetitive behavior, aggression and psychotic episodes (Yalcin-Cakmakli et al, 2014). Other reports showed that the examined patients developed delusions, addictive behavior, impulse control disorder or aggression upon levodopa treatment, while two other patients showed a good response to medication but with treatment-induced dyskinesias (Lorenzo-Betancor et al, 2020;Yoo et al, 2020). Studies that performed tomographic imaging studies on PARK15 patients to determine the availability of dopamine transporter as a marker for nigrostriatal integrity, reported presynaptic defects as the amount of dopamine uptake was significantly reduced (Di Fonzo et al, 2009;Yoo et al, 2020).…”

Section: Introductionmentioning

confidence: 98%

“…Parkinson disease (PD) and parkinsonism‐related disorders have been associated with genetic mutations in PARK loci. Among those, mutations in PARK15 which encodes for FBXO7, have been associated with a recessive and complicated subtype of parkinsonism termed Parkinsonian Pyramidal syndrome (PPS) or PARK15 syndrome (Correa‐Vela et al, 2020; Di Fonzo et al, 2009; Jin et al, 2020; Lohmann et al, 2015; Lorenzo‐Betancor et al, 2020; Shojaee et al, 2008; Wang et al, 2021; Wei et al, 2018; Yalcin‐Cakmakli et al, 2014; Yoo et al, 2020; Zhao et al, 2020). Affected individuals with PARK15 mutations develop the disease as early as in their teens and present with a wide spectrum of signs and symptoms.…”

Section: Introductionmentioning

confidence: 99%

Loss of the parkinsonism‐associated protein FBXO7 in glutamatergic forebrain neurons in mice leads to abnormal motor behavior and synaptic defects

Wang,

Joseph,

Vingill

et al. 2023

Journal of Neurochemistry

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Mutations in PARK15, which encodes for the F‐box protein FBXO7 have been associated with Parkinsonian Pyramidal syndrome, a rare and complex movement disorder with Parkinsonian symptoms, pyramidal tract signs and juvenile onset. Our previous study showed that systemic loss of Fbxo7 in mice causes motor defects and premature death. We have also demonstrated that FBXO7 has a crucial role in neurons as the specific deletion in tyrosine hydroxylase‐positive or glutamatergic forebrain neurons leads to late‐onset or early‐onset motor dysfunction, respectively. In this study, we examined NEX‐Cre;Fbxo7fl/fl mice, in which Fbxo7 was specifically deleted in glutamatergic projection neurons. The effects of FBXO7 deficiency on striatal integrity were investigated with HPLC and histological analyses. NEX‐Cre;Fbxo7fl/fl mice revealed an increase in striatal dopamine concentrations, changes in the glutamatergic, GABAergic and dopaminergic pathways, astrogliosis and microgliosis and little or no neuronal loss in the striatum. To determine the effects on the integrity of the synapse, we purified synaptic membranes, subjected them to quantitative mass spectrometry analysis and found alterations in the complement system, endocytosis and exocytosis pathways. These neuropathological changes coincide with alterations in spontaneous home cage behavior. Taken together, our findings suggest that FBXO7 is crucial for corticostriatal projections and the synaptic integrity of the striatum, and consequently for proper motor control.image

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“…Since 2008, when the first case of Parkinsonian pyramidal syndrome in an Iranian family was linked to a mutation in FBXO7, many other pathological recessive mutations of FBXO7 have been identified [3][4][5][6]. These mutations are clustered at the N-and C-terminal domains of Fbxo7, and a wide range of symptoms have been reported [2,[6][7][8][9][10][11][12][13][14][15][16][17][18]. The age of the onset is also variable with cases arising in childhood and adolescence to young adults and older patients.…”

Section: Introductionmentioning

confidence: 99%

Study of an FBXO7 patient mutation reveals Fbxo7 and PI31 co‐regulate proteasomes and mitochondria

Al Rawi,

Simpson,

Agnarsdóttir

et al. 2024

The FEBS Journal

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Mutations in FBXO7 have been discovered to be associated with an atypical parkinsonism. We report here a new homozygous missense mutation in a paediatric patient that causes an L250P substitution in the dimerisation domain of Fbxo7. This alteration selectively ablates the Fbxo7‐PI31 interaction and causes a significant reduction in Fbxo7 and PI31 levels in patient cells. Consistent with their association with proteasomes, patient fibroblasts have reduced proteasome activity and proteasome subunits. We also show PI31 interacts with the MiD49/51 fission adaptor proteins, and unexpectedly, PI31 acts to facilitate SCFFbxo7‐mediated ubiquitination of MiD49. The L250P mutation reduces the SCFFbxo7 ligase‐mediated ubiquitination of a subset of its known substrates. Although MiD49/51 expression was reduced in patient cells, there was no effect on the mitochondrial network. However, patient cells show reduced levels of mitochondrial function and mitophagy, higher levels of ROS and are less viable under stress. Our study demonstrates that Fbxo7 and PI31 regulate proteasomes and mitochondria and reveals a new function for PI31 in enhancing the SCFFbxo7 E3 ubiquitin ligase activity.

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Novel compound heterozygous FBXO7 mutations in a family with early onset Parkinson's disease

Cited by 10 publications

References 13 publications

Comprehensive analysis of next-generation sequencing data in COVID-19 and its secondary complications

Comprehensive analysis of next-generation sequencing data in COVID-19 and its secondary complications

Loss of the parkinsonism‐associated protein FBXO7 in glutamatergic forebrain neurons in mice leads to abnormal motor behavior and synaptic defects

Study of an FBXO7 patient mutation reveals Fbxo7 and PI31 co‐regulate proteasomes and mitochondria

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