FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome

Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milano, Lombardy, Italy
Neurology (Impact Factor: 8.29). 12/2008; 72(3):240-5. DOI: 10.1212/01.wnl.0000338144.10967.2b
Source: PubMed


The combination of early-onset, progressive parkinsonism with pyramidal tract signs has been known as pallido-pyramidal or parkinsonian-pyramidal syndrome since the first description by Davison in 1954. Very recently, a locus was mapped in a single family with an overlapping phenotype, and an FBXO7 gene mutation was nominated as the likely disease cause.
We performed clinical and genetic studies in two families with early-onset, progressive parkinsonism and pyramidal tract signs.
An FBXO7 homozygous truncating mutation (Arg498Stop) was found in an Italian family, while compound heterozygous mutations (a splice-site IVS7 + 1G/T mutation and a missense Thr22Met mutation) were present in a Dutch family. We also found evidence of expression of novel normal splice-variants of FBXO7. The phenotype associated with FBXO7 mutations consisted of early-onset, progressive parkinsonism and pyramidal tract signs, thereby matching clinically the pallido-pyramidal syndrome of Davison. The parkinsonism exhibits varying degrees of levodopa responsiveness in different patients.
We conclusively show that recessive FBXO7 mutations cause progressive neurodegeneration with extrapyramidal and pyramidal system involvement, delineating a novel genetically defined entity that we propose to designate as PARK15. Understanding how FBXO7 mutations cause disease will shed further light on the molecular mechanisms of neurodegeneration, with potential implications also for more common forms of parkinsonism, such as Parkinson disease and multiple system atrophy.

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    • "Several gene loci have been demystified by either linkage analysis or genomewide association studies. A total of 18 PD loci have been nominated through linkage analysis (PARK1-15) or genomewide association studies (PARK16-18) (Gasser et al. 1998, Hicks et al. 2002, Pankratz et al. 2003, 2009, Strauss et al. 2005, Farrer 2006, Belin and Westerlund 2008, Lautier et al. 2008, Di Fonzo et al. 2009, Paisan-Ruiz et al. 2009, Satake et al. 2009, Hamza et al. 2010). "
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    ABSTRACT: Parkinson’s disease is the second most common neurodegenerative disease which affects almost 1% of the population above the age of 60. It is is characterized by loss of dopaminergic neurons in the striatum and substantia nigra, coupled with the formation of intracellular Lewy bodies in degenerating neurons. Recent evidence suggests endoplasmic reticulum stress as a common and prominent occurrence in the progression of Parkinson’s disease pathogenesis in the affected human brain. One of the cellular defense mechanism to combat endoplasmic reticulum stress due to excessive protein accumulation is through activation of the unfolded protein response pathway. In this review we focus on the impact and role of this unfolded protein response as a causative factor of Parkinson’s disease leading to neurodegeneration.
    Acta neurobiologiae experimentalis 04/2015; 75:1-26. · 1.29 Impact Factor
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    • "The etiology of the maternal grandfather is controversial. Homozygous or compound heterozygous mutations were reported as pathological [2]. The grandfather is expected to have no parkinsonism due to the FBX07eR498X mutation as he is a heterozygous carrier like his daughter and his consanguineous son-in-law. "
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    ABSTRACT: Objective FBXO7 mutations (PARK 15), first reported in 2008, are among the monogenic causes of early-onset parkinsonism. Classically, PARK 15 was suggested to correspond to previously described pallido-pyramidal syndrome. Here, we report clinical and genetic findings in a unique family of Kurdish origin with an FBXO7 mutation and presenting with diverse clinical phenotypes. Methods The family consisted of 14 members (12 offspring) of whom three were affected. Two of these three siblings were examined in our clinic. DNA samples from the index case and his elder sister were subjected to homozygosity mapping and exomic sequencing. Results The index case had progressive speech problems, severe apathy, chorea, and tics at presentation and developed very mild parkinsonism and postural instability after 3 years. His sister had young-onset asymmetric tremor-dominant parkinsonism with some atypical features, such as early development of postural instability, tics, and tachyphemic speech. She died of an akinetic-rigid condition and had not developed chorea. A homozygous R498X mutation was found in both patients (NM_012179; chr22:31,224,440). This result was further confirmed by Sanger sequencing in both patients, their consanguineous parents, and their maternal grandfather; the latter three were found to be heterozygous for the mutation (c.C1492T; p.R498X). Conclusions The family presented here broadens the clinical spectrum of parkinsonism to include tics and chorea, in addition to the parkinsonian-pyramidal phenotype, in connection with FBXO7 mutations and points to an intrafamilial phenotypic variation.
    Parkinsonism & Related Disorders 11/2014; 20(11). DOI:10.1016/j.parkreldis.2014.07.016 · 3.97 Impact Factor
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    • "His younger brother, designated NAPO7, carried the same ATP13A2 mutation and showed mild mental retardation but no clinically obvious Parkinsonism. His V′′3 ratio was 40% lower than normal in the caudate and 65% lower in the putamen, consistent with the fact that mild retardation can be an initial symptom of PD [9, 32]. These results suggest that combining genotyping of PD susceptibility genes with positron emission tomography or SPECT may improve diagnosis of early-stage PD, especially in subclinical patients. "
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    ABSTRACT: Parkinson's disease (PD) is a major neurodegenerative disorder for which the etiology and pathogenesis remain as elusive as for Alzheimer's disease. PD appears to be caused by genetic and environmental factors, and pedigree and cohort studies have identified numerous susceptibility genes and loci related to PD. Autosomal recessive mutations in the genes Parkin, Pink1, DJ-1, ATP13A2, PLA2G6, and FBXO7 have been linked to PD susceptibility. Such mutations in ATP13A2, also named PARK9, were first identified in 2006 in a Chilean family and are associated with a juvenile-onset, levodopa-responsive type of Parkinsonism called Kufor-Rakeb syndrome (KRS). KRS involves pyramidal degeneration, supranuclear palsy, and cognitive impairment. Here we review current knowledge about the ATP13A2 gene, clinical characteristics of patients with PD-associated ATP13A2 mutations, and models of how the ATP13A2 protein may help prevent neurodegeneration by inhibiting α-synuclein aggregation and supporting normal lysosomal and mitochondrial function. We also discuss another ATP13A2 mutation that is associated with the family of neurodegenerative disorders called neuronal ceroid lipofuscinoses (NCLs), and we propose a single pathway whereby ATP13A2 mutations may contribute to NCLs and Parkinsonism. Finally, we highlight how studies of mutations in this gene may provide new insights into PD pathogenesis and identify potential therapeutic targets.
    BioMed Research International 08/2014; 2014:371256. DOI:10.1155/2014/371256 · 3.17 Impact Factor
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