Complete mitochondrial genomics is an effective tool for studying the demographic history of human populations, but there is still a deficit of mitogenomic data in European populations. In this ...paper, we present results of study of variability of 80 complete mitochondrial genomes in two Hungarian populations from eastern part of Hungary (Szeged and Debrecen areas). The genetic diversity of Hungarian mitogenomes is remarkably high, reaching 99.9% in a combined sample. According to the analysis of molecular variance (AMOVA), European populations showed a low, but statistically significant level of between-population differentiation (
Fst
= 0.61%,
p
= 0), and two Hungarian populations demonstrate lack of between-population differences. Phylogeographic analysis allowed us to identify 71 different mtDNA sub-clades in Hungarians, sixteen of which are novel. Analysis of ancestry-informative mtDNA sub-clades revealed a complex genetic structure associated with the genetic impact of populations from different parts of Eurasia, though the contribution from European populations is the most pronounced. At least 8% of ancestry-informative haplotypes found in Hungarians demonstrate similarity with East and West Slavic populations (sub-clades H1c23a, H2a1c1, J2b1a6, T2b25a1, U4a2e, K1c1j, and I1a1c), while the influence of Siberian populations is not so noticeable (sub-clades A12a, C4a1a, and probably U4b1a4).
There is increasing evidence that several mitochondrial abnormalities are present in the brains of patients with Alzheimer's disease (AD). Decreased alpha-ketoglutarate dehydrogenase complex (αKGDHc) ...activity was identified in some patients with AD. The αKGDHc is a key enzyme in the Krebs cycle. This enzyme is very sensitive to the harmful effect of reactive oxygen species, which gives them a critical role in the Alzheimer and mitochondrial disease research area. Previously, several genetic risk factors were described in association with AD. Our aim was to analyze the associations of rare damaging variants in the genes encoding αKGDHc subunits and AD. The three genes (
,
,
) encoding αKGDHc subunits were sequenced from different brain regions of 11 patients with histologically confirmed AD and the blood of further 35 AD patients. As a control group, we screened 134 persons with whole-exome sequencing. In all subunits, a one-one rare variant was identified with unknown significance based on American College of Medical Genetics and Genomics (ACMG) classification. Based on the literature research and our experience, R263H mutation in the
gene seems likely to be pathogenic. In the different cerebral areas, the αKGDHc mutational profile was the same, indicating the presence of germline variants. We hypothesize that the heterozygous missense R263H in the
gene may have a role in AD as a mild genetic risk factor.
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with unknown genetic and environmental causation in most of the affected individuals. On the other hand, there are a growing ...number of ASD-associated syndromes, where the exact genetic origin can be revealed. Here we report a method, which included the targeted next generation sequencing (NGS) and filtering of 101 ASD associated genes, followed by database search. Next, RNA sequencing was used to study the region of interest at the transcriptional level. Using this workflow, we identified a de novo mutation in the euchromatic histone-lysine N-methyltransferase 1 gene (EHMT1) of an autistic patient with dysmorphisms. Sequencing of EHMT1 transcripts showed that the premature termination codon (Trp1138Ter) created by a single nucleotide change elicited nonsense-mediated mRNA decay, which led to haploinsufficiency already at the transcriptional level. Database and literature search provided evidence that this mutation caused Kleefstra syndrome (KS), which was confirmed by the presence of the disorder-specific phenotype in the patient. We provide a proof of principle that the implemented method is capable to elucidate the genetic etiology of individuals with syndromic autism. The novel mutation detected in the EHMT1 gene is responsible for KS's symptoms. In addition, further genetic factors might be involved in the ASD pathogenesis of the patient including a missense DPP6 mutation (Arg322Cys), which segregated with the autistic phenotype within the family.
•We developed a NGS-based workflow to screen for syndromic causes of autism.•A pathogenic, de novo mutation was found in an autistic patient with dysmorphisms.•The mutation leads haploinsufficiency of EHMT1 mRNA and causes Kleefstra syndrome.•A DPP6 missense variant segregated with the autism within the patient's family•Multiple genetic factors might contribute to autistic syndromes of KS patients.
The protein product of the nuclear-encoded POLG gene plays a key role in the maintenance of mitochondrial DNA replication, and its failure causes multi-system diseases with varying severity. The ...clinical spectrum is extremely wide, and the most common symptoms include ptosis, myoclonus, epilepsy, myopathy, sensory ataxia, parkinsonism, cognitive decline and infertility. Now, it is known that mitochondrial dysfunction in Parkinson's disease plays a key role in the loss of dopaminergic neurons in the substantia nigra. Therefore, changes in the POLG gene may influence the development of various hereditary neurodegenerative diseases, including monogenic parkinsonism. However, only limited information is available on the relationship between Parkinson's disease and POLG gene and until now, there are no available data about the Hungarian population. In our study, we performed a next-generation sequencing study of 67 Hungarian patients with parkinsonism and analyzed the potentially damaging alterations in the POLG gene. 3 patients have been identified with a potential pathogen variant. In this study, we would like to call attention to the fact that during the differential diagnosis of parkinsonism, the possible involvement of POLG gene should be kept in mind. Especially in the presence of additional symptoms, such as ophthalmoparesis, non-vascular white matter lesions, psychiatric comorbidity, and relatively early age of onset, the POLG gene should be taken into consideration. Based on previous data from the literature and our own experience, we have summarized a possible diagnostic approach for POLG-associated parkinsonism. Orv Hetil. 2020; 161(20): 821-828.
The anti-apoptotic gene replacements could be an option in preventing hypoxia-induced neuronal loss. In this paper we tested the effect of anti-apoptosis (bcl-2 and bcl-XL) gene transfer on cell ...plasticity. Nestin, synapsin-1 and c-fos genes and proteins expression were measured in PC12 cells in normal condition, and after hypoxia/re-oxygenation. Gene delivery results a significant increase in both bcl-2 and bcl-XL gene expression. Hypoxia (1h)/re-oxygenation (24h) have a detrimental effect upon cultured cells by increasing the pro-apoptotic, bax gene and protein expression. Bcl-2 or bcl-XL gene delivery resulted in a significant increase in and the cellular levels of the corresponding mRNAs and proteins. Bcl-2 gene augmented the nestin gene and protein expression which has been compromised previously by the hypoxic event. Similarly c-fos mRNA and protein expression decreased significantly after hypoxia, while the anti-apoptotic gene treatment normalized c-fos expression. Synapsin-1 gene or protein expression remained about on the same level under normoxic conditions or following hypoxia after gene treatment.
We can conclude that anti-apoptotic gene transfers activate neuronal plasticity proteins nestin and c-fos. This link on anti-apoptotic proteins and cell plasticity is a new finding.
Abstract We report the case of a 29 year old woman with a complex movement disorder syndrome due to the combination of coexisting pathological triplet repeat expansions of huntingtin and ATXN8 genes. ...The disease course was characterized by mental disturbances including cognitive decline and changes in personality starting at the age of 12 years, followed by twisting motions, intentional tremor and gait ataxia. Later Parkinsonian symptoms of micrographia, bradykinesia, muscle rigidity and mental decline became dominant. Brain MRI showed hypoplasia of the nucleus caudatus and generalized atrophy; MR spectroscopy revealed a decrease of all typical metabolites except for an increased level of lactate and acetate. Therapeutic trials with pramipexole, ropinirole and tetrabenazine showed no benefit, while levetiracetam caused agitation and hallucinations. We discuss phenotype–genotype correlation and the rule of triplet repeat expansions of gene ATXN8.
Introduction
Early-onset dementias (EOD) are predominantly genetically determined, but the underlying disease-causing alterations are often unknown. The most frequent forms of EODs are early-onset ...Alzheimer’s disease (EOAD) and frontotemporal dementia (FTD).
Patients
This study included 120 Hungarian patients with EOD (48 familial and 72 sporadic) which had a diagnosis of EOAD (
n
= 49), FTD (
n
= 49), or atypical dementia (
n
= 22).
Results
Monogenic dementia was detected in 15.8% of the patients. A pathogenic hexanucleotide repeat expansion in the
C9ORF72
gene was present in 6.7% of cases and disease-causing variants were detected in other known AD or FTD genes in 6.7% of cases (
APP
,
PSEN1
,
PSEN2
,
GRN
). A compound heterozygous alteration of the
TREM2
gene was identified in one patient and heterozygous damaging variants in the
CSF1R
and
PRNP
genes were detected in two other cases. In two patients, the coexistence of several heterozygous damaging rare variants associated with neurodegeneration was detected (1.7%). The
APOE
genotype had a high odds ratio for both the
APOE
ɛ4/3 and the ɛ4/4 genotype (OR = 2.7 (95%CI = 1.3–5.9) and OR = 6.5 (95%CI = 1.4–29.2), respectively). In
TREM2
,
SORL1
, and
ABCA7
genes, 5 different rare damaging variants were detected as genetic risk factors. These alterations were not present in the control group.
Conclusion
Based on our observations, a comprehensive, targeted panel of next-generation sequencing (NGS) testing investigating several neurodegeneration-associated genes may accelerate the path to achieve the proper genetic diagnosis since phenotypes are present on a spectrum. This can also reveal hidden correlations and overlaps in neurodegenerative diseases that would remain concealed in separated genetic testing.
Abstract Background Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases with progressive lower limb spasticity and weakness. The ...aim of this study is to determine the frequency of different SPG mutations in Hungarian patients, and to provide further genotype-phenotype correlations for the known HSP causing genes. Methods We carried out genetic testing for 58 probands with clinical characteristics of HSP. For historical reasons, three different approaches were followed in different patients: 1) Sanger sequencing of ATL1 and SPAST genes, 2) whole exome, and 3) targeted panel sequencing by next generation sequencing. Results Genetic diagnosis was established for 20 probands (34.5%). We detected nine previously unreported mutations with high confidence for pathogenicity. The most frequently affected gene was SPAST with pathogenic or likely pathogenic mutations in 10 probands. The most frequently detected variant in our cohort was the SPG7 p.Leu78*, observed in four probands. Altogether five probands were diagnosed with SPG7. Additional mutations were detected in SPG11 , ATL1 , NIPA1 , and ABCD1. Conclusion This is the first comprehensive genetic epidemiological study of patients with HSP in Hungary. Next generation sequencing improved the yield of genetic diagnostics in this disease group even when the phenotype was atypical. However, considering the frequency of the HSP-causing gene defects, SPG4, the most common form of the disease, should be tested first to be cost effective in this economic region.
The A3243G mutation in the mitochondrial tRNALeu ⁽UUR⁾ gene is one of the most common causes of mitochondrial DNA related disorders. Originally it was described in MELAS syndrome (Mitochondrial ...Encephalomyopathy, Lactic acidosis, Stroke-like episodes), later it had been found to be associated with various phenotypes. In our study the mutation frequency of the A3243G mtDNA mutation was investigated in patients with maternal sensoneural hearing loss, stroke-like episodes, ataxia and myopathy with undetermined etiology. We screened 631 Hungarian patients in North-East, South-West and Central Hungary between 1999 and 2008 for this mutation. The mtDNA analysis was performed from blood and/or muscle tissue. The A3243G substitution was present in 6 patients in heteroplasmic form. The segregation analysis detected 8 further cases. The frequency of the A3243G mutation was 2.22% in the investigated patients. The A3243G mutation frequency in Hungary does not differ significantly from other countries using similar patient selection criteria, however in Finland a higher mutation rate was found. In studies investigated the mutation frequency of this mutation in diabetes mellitus similarly wide variety was detected as well. We conclude that the study design has a huge impact on the result of the genetic epidemiological investigation analyzing the mutation frequency of the A3243G mutation due to the broad clinical phenotype and the different mutation load in different tissues.
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