Nihan Erginel-Unaltuna

Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy

Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression.

ADAM-9, ADAM-15, and ADAM-17 are upregulated in macrophages in advanced human atherosclerotic plaques in aorta and carotid and femoral arteries—Tampere vascular study

Background and aims. The expression of disintegrin and metalloprotease ADAM-9, ADAM-15, and ADAM-17 has been associated with cell-cell, cell-platelet, and cell-matrix interactions and inflammation. They are possibly implicated in the pathophysiology of atherosclerosis. Methods and results. Whole-genome expression array and quantitative real-time polymerase chain reaction (PCR) analysis confirmed that ADAM-9, ADAM-15, and ADAM-17 are upregulated in advanced human atherosclerotic lesions in samples from carotid, aortic, and femoral territories compared to samples from internal thoracic artery (ITA) free of atherosclerotic plaques. Western analysis indicated that the majority of these ADAMs were in the catalytically active form. ADAM-9, ADAM-15, and ADAM-17-expressing cells were shown to co-localize with CD68-positive cells of monocytic origin in the atherosclerotic plaques using immunohistochemistry and double-staining immunofluorescence analysis. Co-localization was demonstrated in all vascular territories. In the carotid territory, cells expressing the ADAMs co-distributed also with smooth muscle cells and, in femoral territory, with CD31-positive endothelial cells, indicating that the ADAM expression pattern depends on vascular bed territory. Conclusions. Present findings provide strong evidence for the involvement of catalytically active ADAM-9, ADAM-15, and ADAM-17 in advanced atherosclerosis, most notably associated with cells of monocytic origin.

Gender-modulated impact of apolipoprotein A5 gene (APOA5) -1131T>C and c.56C>G polymorphisms on lipids, dyslipidemia and metabolic syndrome in Turkish adults.

Abstract Background: Apolipoprotein A5 (APOA5) gene polymorphisms are usually associated with plasma triglyceride levels. We evaluated the relationship of the APOA5 −1131T>C and c.56C>G polymorphisms [single nucleotide polymorphism (SNP)] with serum lipids, dyslipidemia [low high-density lipoprotein (HDL)/high triglyceride] and the risk for metabolic syndrome (MS) in the Turkish Adult Risk Factor study. Methods: We genotyped SNPs using the Taqman allelic discrimination assays in 1564 Turkish adults (51.4% female, mean age 54.1±11.6 years). MS and dyslipidemia were defined using the criteria of the National Cholesterol Education Program. Results: For both SNPs, rare allele carriers had significantly higher fasting triglyceride levels in both genders, except the c.56G allele in men. The −1131C allele was associated with lower HDL cholesterol (HDL-C) levels in women. In relation to dyslipidemia, the c.56C>G and haplotype 1 had significant gender-genotype interactions (p<0.05). Otherwise, both SNPs were significantly associated with dyslipidemia after adjustment for risk factors in women. After similar adjustment, non-carriers of the haplotype 1 (odds ratio=4.1, p=0.003) increased the MS risk in women. However, no significant associations emerged between SNPs and HDL-C, dyslipidemia or MS in a similar analysis in men. Conclusions: Excess risk for low HDL-C, dyslipidemia and MS is associated with the rare alleles of the APOA5 SNPs and non-carriers of common haplotype in women. Clin Chem Lab Med 2008;46:778–84.

Endothelial dysfunction in patients with asthma: the role of polymorphisms of ACE and endothelial NOS genes.

Objectives. Polymorphisms of the angiotensin converting enzyme (ACE) and endothelial nitric oxide (eNOS) genes have been implicated in asthma pathogenesis. Angiotensin II and NO have important roles in maintaining vascular tone. In this study, the relationship between endothelial dysfunction and ACE and eNOS gene polymorphisms was investigated in patients with asthma. Methods. This cross‐sectional, controlled study was conducted at the Yedikule Chest Disease Hospital and Cardiology Center in a University Hospital. Forty‐nine patients with asthma (18 male, 31 female; mean age: 33 ± 12 years) and 49 age‐ and sex‐matched healthy controls (20 male, 29 female; mean age: 30 ± 8 years) were included. Pulmonary function tests and flow‐mediated dilatation of the brachial artery [endothelium dependent dilatation (EDD)] were examined by high‐resolution ultrasonography. The ACE and eNOS genotypes were determined by PCR. Results. Asthma patients showed lower EDD (12 ± 6% vs. 22 ± 6%, p < 0.001) as compared to controls. The EDD was correlated with both predicted value of FEV1 (r = 0.31, p = 0.04) and predicted value of FVC (r = 0.37, p = 0.013). Conversely, EDD values in patients with moderate asthma were significantly lower than those in patients with mild asthma (10.1 ± 5.2% vs. 14.1 ± 5.7%, p = 0.017). However, the ACE and eNOS genotype distribution was not significantly different between controls and asthma groups. Furthermore, EDD was not associated with both gene polymorphism of ACE and eNOS. Conclusion. Patients with asthma have decreased vasodilatatory response to shear stress (EDD). Decreased EDD is correlated with the severity of asthma, but not with the distribution of ACE and eNOS genotypes.

Distribution of the M129V polymorphism of the prion protein gene in a Turkish population suggests a high risk for Creutzfeldt-Jakob disease.

A polymorphism (M129V) at codon 129 of the prion protein gene (PRNP) results in either a methionine residue (Met) or a valine residue (Val) and is known to determine susceptibility for the development of sporadic or acquired Creutzfeldt-Jakob disease (CJD). The distributions of M129V genotypes and alleles in various general populations have been reported and there are clear differences between Western Europeans and East Asians. We analysed the coding sequence of the PRNP gene in 100 healthy Turkish subjects to determine whether the distributions of the M129V genotypes and alleles or other PRNP gene variants in the Turkish population differ from those in other normal populations. Three known polymorphisms but no other gene variants were detected in the PRNP coding sequence of the Turkish individuals. Genotype frequencies at codon 129 were 57% Met/Met, 34% Met/Val and 9% Val/Val, with an allele frequency of 0.740 : 0.260 Met:Val. These distributions are considerably different from those reported for other normal populations residing in Western Europe and East Asia, except in Crete. The higher frequency of 129 Met-homozygotes in Turkey than in Western Europe suggests that the Turkish are at greater risk of developing CJD.

Endothelial function and endothelial nitric oxide synthase intron 4a/b polymorphism in primary hyperparathyroidism.

Background and aim: Patients with symptomatic primary hyperparathyroidism (pHT) have increased cardiovascular morbidity and mortality. Endothelial nitric oxide synthase (eNOS) intron 4a/b polymorphism is associated with coronary artery disease and hypertension in various populations. Our aim is to evaluate endothelial function in patients with pHT during pre-operative hypercalcemic and post-operative normocalcemic periods and to determine whether intron 4a/b polymorphism of eNOS gene influences endothelial function. Subjects and Methods: Forty patients with pHT (age 48.48±11.64 yr) were examined pre-operatively and reexamined 5.8±1.9 months after parathyroidectomy. Forty-three healthy subjects (age 47.13±8.14 yr) were served as control group. Endothelial function was determined by flow-mediated dilation of brachial artery (FMD). eNOS4a/b polymorphism was detected by polymerase chain reaction. Results: FMD was significantly lower in patients pre-operatively compared with controls (8.48±1.78% vs 19.49±2.34%, p<0.001). FMD improved significantly after parathyroidectomy (16.19±2.16%, p<0.001 compared with pre-operative measurements), but was still significantly lower than controls (p<0.001). The distribution of eNOS4a/b genotype frequencies was not significantly different between patients and controls. Logistic regression analysis showed that increased serum calcium (>2.47 mmol/l) and PTH concentrations (>7.75 pmol/l) were significant independent predictors of lower FMD (<16.7%). ENOS4a/b polymorphism did not enter in this model. Conclusion: Impaired endothelial function in patients with pHT improves after successful parathyroid surgery. No compelling data are evident to suggest that eNOS4a/b polymorphism modifies the endothelial function in patients with pHT.

A new F‐box protein 7 gene mutation causing typical Parkinson's disease

Recessive mutations in the F‐box protein 7 gene (FBXO7; PARK15) have been identified as a cause of the parkinsonian‐pyramidal syndrome. Here, we report clinical and genetic findings in a Turkish family with novel FBXO7 mutations.

Association of C-reactive protein (CRP) gene allelic variants with serum CRP levels and hypertension in Turkish adults

OBJECTIVE Serum C-reactive protein (CRP) is an independent risk factor for cardiovascular disease and metabolic syndrome (MetS). The aim of this study was to analyze the CRP gene allelic variations in the Turkish adult risk factor (TARF) study and relate them with serum CRP levels as well as MetS and its components. METHODS We analyzed CRP gene polymorphisms (-286C>T>A [rs3091244], +1444C>T [rs1130864], +1059G>C [rs1800947], and +1846G>A [rs1205]) as well as their haplotypes, in addition to measuring CRP levels (n=1138) and collecting risk factor data from 1987 adults (mean age 54.3+/-11.9 years, 51.3% women) participating in the TARF Study. MetS was defined by using the criteria of the National Cholesterol Education Program modified for pre-diabetes and in men for abdominal obesity. RESULTS After adjustment for the major cardiovascular risk factors, four CRP SNPs (-286C>T>A, +1059G>C, +1444C>T, and +1846G>A) were significantly associated with serum CRP levels in women (p<0.05), whereas the -286C>T>A and +1444C>T polymorphisms were associated with CRP levels in men (p<0.05). The haplotype analyses revealed four common CRP haplotypes. The haplotype 1 (CGCA) in women and the haplotype 3 (TGTG) in men were associated with serum CRP levels and hypertension (p<0.05). However, no haplotype association was observed for MetS or its components. CONCLUSION CRP gene allelic variation is associated with serum CRP levels as well as hypertension in Turkish adults.

Association of a polymorphism of the ecNOS gene with myocardial infarction in a subgroup of Turkish MI patients.

In this study we examined a possible association between a 27 base pair (bp)‐repeat polymorphism in intron 4 of the ecNOS gene and myocardial infarction (MI) in a subgroup of the Turkish population. We compared MI and control groups for the frequencies of the ecNOS alleles and their genotypes. The frequency of the ecNOS 4a/a and 4a/b genotypes was found to be significantly higher in the MI group than in the control group. Interestingly, the frequency of the ecNOS 4a/b polymorphism was found to be significantly higher in the selected MI group (patients with no known secondary risk factors) than in the control and non‐selected MI group. We found that the patients with MI had the frequency of the a/a genotype 4.3%, of the a/b genotype 26.6% and the b/b genotype 69.1%. The controls, however, showed only 0.6% for a/a, 18.0% for a/b and 81.4% for the b/b genotype (P < 0.001; χ2 = 13.626). In this study, we show that myocardial infarction is associated with one subtype of ecNOS gene polymorphism.

Ventricular pre-excitation and cardiac hypertrophy mimicking hypertrophic cardiomyopathy in a Turkish family with a novel PRKAG2 mutation

Mutations in PRKAG2, the gene for the γ2 regulatory subunit of AMP‐activated protein kinase, cause cardiac hypertrophy and electrophysiological abnormalities. We identified a novel mutation in PRKAG2 causing familial ventricular pre‐excitation and severe cardiac hypertrophy.