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Brain MR Spectroscopy Changes Precede Frontotemporal Lobar Degeneration Phenoconversion in Mapt Mutation Carriers.

BACKGROUND AND PURPOSE: The objective of this study was to longitudinally investigate the trajectory of change in 1 H MRS measurements in asymptomatic MAPT mutation carriers who became symptomatic during follow-up, and to determine the time at which the neurochemical alterations accelerated during disease progression. METHODS: We identified eight MAPT mutations carriers who transitioned from asymptomatic to symptomatic disease during follow-up. All participants were longitudinally followed with an average of 7.75 years (range 4-11 years) and underwent two or more single voxel 1 H MRS examinat

Mutational activation of FGFR3: no involvement in the development of renal cell carcinoma.

BACKGROUND: Somatic point mutations in the fibroblast growth factor receptor 3 (FGFR3) gene have been identified in certain types of urological cancers, especially urothelial carcinoma of the bladder and the renal pelvis, and could be correlated with a favourable outcome. However, comprehensive data on the FGFR3 mutation status in renal cell carcinoma (RCC) are still missing. METHODS: In order to investigate a possible role for FGFR3 mutations in renal cell carcinogenesis, we performed a sequence-based mutational analysis of FGFR3 in 238 primary RCC. The cohort obtained the common RCC subtype…

Вскрытие болезни Креуцфельда-Якоба с V180I мутации гена ПрП и патологии типа Альцгеймера.

Мы сообщаем о вскрытии болезни Креуцфельдта-Якоба с кодоном 180-точечной мутации гена прионового белка (PRNP). У 77-летней женщины развилась походка, за которой последовало слабоумие и атаксия конечностей/транквилизаторов. Она стала кинетической и немой через 18 месяцев и умерла от пневмонии через 26 месяцев после заболевания. Анализ гена PRNP выявил мутации кодона 180 точек. Посмертный осмотр выявил заметный гпондиоз, нервную потерю и астроцитический глиоз в коре головного мозга. В лимбической коре и базальной ганглии наблюдались незначительные и умеренные губки и нейронные потери. В гиппокам

Совпадение в аннотации оригинала
We report an autopsy case of Creutzfeldt-Jakob disease with a codon 180 point mutation of the prion protein gene (PRNP). A 77-year-old woman developed gait instability, followed by dementia and limb/truncal ataxia. She became akinetic and mute 18 months and died of pneumonia 26 months after the disease onset. Analysis of the PRNP gene revealed a codon 180 po…

SNP identification, haplotype analysis, and parental origin of mutations in TSC2.

Inactivating mutations in the TSC2 gene, consisting of 41coding exons in 40 kb on 16p13, cause the hamartoma syndrome tuberous sclerosis. Du … possible in 12 sporadic cases, and indicated that the mother was the parent of origin in 7 cases (3 point mutations, 2 small deletions, 2 large deletions), while the father was in 5 cases (2 point mutations, 3 small deletions). We conclude that TSC2 mutations occur at substantial frequency on both the maternally and paternally derived TSC2 alleles, in contrast t …

Multiple symmetric lipomatosis: evidence for mitochondrial dysfunction.

OBJECTIVES: : To assess the presence of mitochondria! dysfunction in 18 patients with multiple symmetric lipomatosis (MSL). METHODS: : Electromyography and nerve conduction study were performed in 15 patients with MSL and autonomic tests in 14. Nerve biopsy was done in four patients and muscle biopsy in six. Mitochondrial enzyme activities were measured in six muscle biopsies. We investigated myoclonic epilepsy ragged red fibers (MERRF) point mutation and multiple deletions in mtDNA with PCR, enzyme restriction digestion, and Southern blot analysis in lymphocyte DNA, or in muscle DNA when ava…

Transition mutation in codon 248 of the p53 tumor suppressor gene induced by reactive oxygen species and a nitric oxide-releasing compound.

Exposing the human bronchial epithelial cell line BEAS-2B to the nitric oxide (NO) donor sodium 1-(N,N-diethylamino)diazen-1-ium-1, 2-diolat … tions, suggesting that co-generation of NO and superoxide was responsible for inducing the observed point mutation. DEA/NO potentiated the ability of HX/XO to induce lipid peroxidation as well as DNA single- and double-strand breaks under these conditions, while 0.6 mM DEA/NO in the absence of HX/XO had no significant effect on these parameters. The results show …

Dopa-responsive dystonia: a clinical and molecular genetic study.

We have studied the GTP-cyclohydrolase 1 (GCH-1) gene in 30 patients with the diagnosis of clinically definite (n = 20) or possible (n = 10) dopa-responsive dystonia (DRD) as well as in a child with atypical phenylketonuria due to complete GCH-1 deficiency. A large number of new heterozygote mutations (seven point mutations, two splice site mutations, and one deletion) as well as a new homozygote mutation in the child with atypical phenylketonuria were detected. In addition, two previously described mutations were found in two other cases. We further extended our investigation of GCH-1 to the …

H-ras oncogene activation in invasive UVR-induced corneal sarcomas of the opossum Monodelphis domestica.

Chronic exposure to ultraviolet radiation (UVR) induces corneal sarcomas in the South American opossum Monodelphis domestica. Cell lines are … evidence of H-ras gene amplification or rearrangement. One tumor was heterozygous for an activating point mutation in codon 61 of the H-ras gene; the tumor was also homozygous for a point mutation at an adjacent site in codon 62. These results provide additional evidence for the functional importance and consequent evolutionary conservation of the ras oncogenes.

Functional characterization of a distinct ryanodine receptor mutation in human malignant hyperthermia-susceptible muscle.

Malignant hyperthermia is an inherited autosomal disorder of skeletal muscle in which certain volatile anesthetics and depolarizing muscle relaxants trigger an abnormally high release of Ca2+ from the intracellular Ca2+ store, the sarcoplasmic reticulum. In about 50% of cases, malignant hyperthermia susceptibility is linked to the gene encoding the skeletal muscle ryanodine receptor/Ca2+ release channel (RYR1). To date, eight point mutations have been identified in human RYR1. Although these mutations are thought to lead to an increased caffeine and halothane sensitivity in the contractile res…

Albumin Hawkes Bay; a low level variant caused by loss of a sulphydryl group at position 177.

A slow migrating minor albumin component, representing 5% of total circulating albumin, was detected by routine serum protein electrophoresi … showed the presence of a new peptide of sequence Ala-Ala-Phe-Leu- Leu-Pro-Lys, indicating either a point mutation of 177 Cys-->Phe or the deletion of residues 166-177. DNA sequencing of PCR-amplified DNA confirmed the former Cys-->Phe substitution by indicating a point mutation of C to A at nucleotide position 5185. It appears that the aberrant electrophoretic …

Leber's hereditary optic neuropathy and complex I deficiency in muscle.

We investigated a family with Leber's hereditary optic neuropathy in which affected individuals were homoplasmic for the point mutation of the NADH-dehydrogenase 4 gene of mitochondrial DNA, described by Wallace and colleagues in 1988. The proband had bilateral optic atrophy, tremor, dystonia, and sharply defined lesions in the putamen on magnetic resonance images. Optic atrophy was found in another 3 of 13 investigated relatives on the maternal side. Additional neurological signs were found but only in patients with optic neuropathy. The morphological appearance and the respiratory chain func…

Overview on Therapeutic Options in Uncommon EGFR Mutant Non-Small Cell Lung Cancer (NSCLC): New Lights for an Unmet Medical Need.

The majority of epidermal growth factor receptor (EGFR) mutations (85-90%) are exon 19 deletions and L858R point mutations of exon 21, characterized by high sensitivity to EGFR-tyrosine kinase inhibitors (TKIs). Less is known about uncommon mutations (10-15% of EGFR mutations). The predominant mutation types in this category include exon 18 point mutations, exon 21 L861X, exon 20 insertions, and exon 20 S768I. This group shows a heterogeneous prevalence, partly due to different testing methods and to the presence of compound mutations, which in some cases can lead to shorter overall survival a…

Predicting EGFR mutation status in lung cancer:Proposal for a scoring model using imaging and demographic characteristics.

OBJECTIVE: To determine if a combination of CT and demographic features can predict EGFR mutation status in bronchogenic carcinoma. METHODS: We reviewed demographic and CT features for patients with molecular profiling for resected non-small cell lung carcinoma. Using multivariate logistic regression, we identified features predictive of EGFR mutation. Prognostic factors identified from the logistic regression model were then used to build a more practical scoring system. RESULTS: A scoring system awarding 5 points for no or minimal smoking history, 3 points for tumours with ground glass com

Difficult Cases in the Diagnosis of Thalassemia Syndromes.

Thalassemia syndromes result from a significant reduction in the synthesis of globin chains (α, β, γ, δ). An imbalance between α- and non-α-globin chains underlies β-thalassemia. α-Globin tetramers accumulate and precipitate in erythroid precursors (ineffective erythropoiesis). Hemolysis also plays an important role, shortening the erythrocyte lifespan. α-Thalassemia syndromes are caused by approximately 200 deletions and point mutations, as well as rare large deletions. More than 350 mutations have been identified in β-thalassemia syndromes, the majority of which are point mutations, with rar…

Characteristics of quinolone resistance in Escherichia coli isolated from wildlife in Poland.

The widespread use of quinolones (QNs) in human and veterinary medicine has resulted in the emergence of QN-resistant bacteria. The most common and widespread type of resistance to FQ is the presence of point mutations in the QRDR region and/or PMQR genes. The aim of the study was to analyze the mechanisms of quinolone resistance among E. coli strains isolated from wild animals in Poland. Out of 42 tested isolates, 39 strains had at least one point mutation in the gyrA gene; however, 76.2% of the isolates had at least three mutations in the GyrA and ParC domains, mainly S83L or D87L in the gyr…

Pseudokinase-converting mutation in protein kinase C alpha drives chordoid glioma by pathway rewiring.

Chordoid glioma (ChG) is a rare, low-grade brain tumor characterized by a novel recurrent point mutation, D463H, in the kinase domain of protein kinase C alpha (PKCα). The mutation is invariably an Asp to His substitution, suggesting a unique function beyond catalytic inactivation associated with other cancer-associated PKCα mutations. Here, we show that this mutation converts PKCα into a pseudokinase, abolishing catalytic activity, and, additionally, confers novel scaffolding functions. Activity assays in vitro and in cellulo revealed that PKCαD463H is catalytically inactive and functions as …

NAALAD2 mutations disrupt the fate of photoreceptor cells and retinal pigment epithelial cells during early retinal development.

In recent years, the global incidence of myopia has steadily increased, highlighting the importance of prevention and early intervention, particularly in the absence of effective treatments. Here, we identified a previously unreported mutation in the human N-acetylated alpha-linked acidic dipeptidase 2 (NAALAD2) gene (c.2109 T > G, p.F703L) considered in a Chinese family with pathological myopia (PM). We explored the potential link between NAALAD2 mutation and the development of PM by using the Naalad2 point mutation knock-in mouse models. Through single-cell RNA sequencing, we analyzed the re…

Accuracy of direct mutation testing by TaqMan quantitative polymerase chain reaction for preimplantation genetic diagnosis of recurrent de novo mutations.

OBJECTIVE: To assess the accuracy and allele dropout (ADO) rate of preimplantation genetic testing for monogenic disease (PGT-M) when perfor … at 99.2% (1,705 of 1,719 genotypes). Notably, seven discordant genotypes were attributed to ADO in point mutations, with an additional seven discordances observed in cases involving insertions or deletions. CONCLUSION: Analysis of direct mutation genotyping of trophectoderm biopsies revealed an accuracy of 99.2%.

New murine Niemann-Pick type C models bearing a pseudoexon-generating mutation recapitulate the main neurobehavioural and molecular features of the disease.

Niemann-Pick disease type C (NPC) is a rare neurovisceral disease caused mainly by mutations in the NPC1 gene. This autosomal recessive lysosomal disorder is characterised by the defective lysosomal secretion of cholesterol and sphingolipids. No effective therapy exists for the disease. We previously described a deep intronic point mutation (c.1554-1009 G > A) in NPC1 that generated a pseudoexon, which could be corrected at the cellular level using antisense oligonucleotides. Here, we describe the generation of two mouse models bearing this mutation, one in homozygosity and the other in compou…

Calreticulin mutation profile in Indian patients with primary myelofibrosis.

INTRODUCTION: Somatic mutations in Calreticulin (CALR) have been recently discovered in JAK2/MPL unmutated patients with primary myelofibros … ern (c.1241_1288del) was identified in one (1/9) patient. No case of Type II mutations or scattered point mutations was found in any of these patients. Uni-variate analysis at presentation showed that CALR mutations were significantly associated with younger age (P = 0.003) and larger spleen size (P = 0.001). No significant correlation was found between CALR mut …