DCTN1 encodes the largest subunit of dynactin complex essential in the retrograde axonal transport and cytoplasmic transport of vesicles; mutations in DCTN1 have been reported predominantly in ...individuals with Perry syndrome and, recently, in patients with progressive supranuclear palsy. Our genetic screening of DCTN1 in 79 patients with progressive supranuclear palsy, 100 patients with multiple system atrophy, and 28 patients with dementia with Lewy bodies from Italy revealed only synonymous and intronic variants, suggesting that DCTN1 mutations do not have a key role in the development of atypical parkinsonism in the Italian population.
•Parkinson’s disease (PD) is the second most common neurodegenerative disorder.•Recently, Deng et al. identified a new gene (TMEM230) in a large Canadian Mennonite family with PD.•We evaluate the ...presence of TMEM230 mutations in a cohort of 168 familial PD and 500 control subjects from South Italy.•We found a rare missense variant (p.Ile125Met) in a 64-years old woman and four synonymous variant in our population.•Other studies are needed to clarify the role of the TMEM230 gene in the pathogenesis of Parkinson’s disease.
Summary
Purpose
To report the identification of the T1174S SCN1A (NaV1.1) mutation in a three‐generation family with both epileptic and familial hemiplegic migraine (FHM) phenotypes and clarify the ...pathomechanism.
Methods
The five affected individuals underwent detailed clinical analyses. Mutation analyses was performed by direct sequencing of SCN1A; functional studies by expression in tsA‐201 cells. A computational model was used to compare the effects of T1174S with those of a typical FHM mutation (Q1489K).
Key Findings
The proband had benign occipital epilepsy (BOE); two relatives had simple febrile seizures (FS) and later developed BOE. Two additional relatives had FHM without epilepsy or FS. All affected members and one obliged carrier carried the T1174S mutation. Functional effects were divergent: positive shift of the activation curve and deceleration of recovery from fast inactivation, consistent with loss of function, and increase of persistent current (INaP), consistent with gain of function. The INaP increase was inhibited by dialysis of the cytoplasm, consistent with a modulation. Therefore, as shown by the computational model, T1174S could in some conditions induce overall loss of function, and in others gain of function; Q1489K induced gain of function in all the conditions.
Significance
Modulation of the properties of T1174S can lead to a switch between overall gain and loss of function, consistent with a switch between promigraine end epileptogenic effect and, thus, with coexistence of epileptic and FHM phenotypes in the same family. These findings may help to shed light on the complex genotype–phenotype relationship of SCN1A mutations.
Abstract Parkinson's disease (PD) is characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta. This degeneration leads to bradykinesia, muscular rigidity, ...resting tremor, and postural instability. It affects 1%–2% of the population above the age of 60 years. Recently, 2 studies identified the Asp620Asn mutation in the vacuolar protein sorting 35 ( VPS35 ) gene, and the Arg1205His in the eukaryotic translation initiation factor 4 gamma 1 gene ( EIF4G1 ) were reported to be associated an autosomal dominant form of PD. In this study we screened these mutations in a cohort of 250 South Italy patients with familial PD and 250 control subjects from South Italy. VPS35 Asp620Asn mutation and EIF4G1 Arg1205His mutation were not found in our 250 PD patients. This result, with our previous reports on the absence of mutations in LRRK2 and in SNCA, warrant a continuing search for novel causative genes for PD among South Italy.
COQ2 encodes para-hydroxybenzoate-polyprenyl transferase and, recently, mutations in this gene have been associated with the increase of the risk of multiple system atrophy (MSA) in Japanese cases. ...Subsequently, studies in Asian patients confirmed the role of COQ2 in the development of MSA, while other analysis failed to replicate these results in Caucasian population. We performed genetics screening of COQ2 in 100 MSA Italian patients. We did not find any pathogenic mutations; our results suggest that COQ2 is not a genetic risk factor for MSA in Italian population.
•We screened 100 MSA Italian patients for the COQ2 gene.•We did not identify any pathogenic mutation.•COQ2 is not a genetic risk factor for MSA in Italian population.
Neurodegenerative diseases are often characterized by the presence of intracellular or extracellular protein aggregates in the central nervous system. Mutations of TARDBP gene have been shown to ...cause Amyotrophic Lateral Sclerosis and have been reported to present with clinical heterogeneity including parkinsonism. TDP-43 pathology has been observed across a spectrum of neurodegenerative disorders, including Alzheimer's and Parkinson's disease.
In this study we screened 100 sporadic and 165 familial PD patients and control series (450) for the TARDBP gene. All cases and controls included in this study were born and living in Calabria.
The p.N267S heterozygous mutation was detected in one sporadic PD patient. The p.N267S mutation was not found in a control population of 450 healthy individuals and in our 165 familial PD.
Sequencing of the TARDBP gene in our patient cohort identified one sporadic PD carrying the p.N267S mutation. This is the first analysis of TARDBP mutation in sporadic PD patient from South Italy.
•We screened 100 sporadic and 165 familial PD patients for TARDBP gene.•The p.N267S heterozygous mutation was detected in one sporadic PD patients.•This is the first analysis of TARDBP mutation in sporadic PD patients from South Italy.
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