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Correlative Raman spectroscopy and electron microscopy identifies glycogen rich deposits correlated with local structural defects in long bones of type IV osteogenesis imperfecta patients.

Osteogenesis imperfecta (OI) is a genetic bone disease occurring in approximately 1 in 10,000 births, usually as a result of genetic mutation. OI patients suffer from increased fracture risk and - depending on the severity of the disease - deformation of the limbs, which can even lead to perinatal death. Despite extensive studies, the way in which the genetic mutation is translated into structural and compositional anomalies of the tissue is still an open question. Different observations have been reported, ranging from no structural (or chemical) differences to completely chaotic bone structu

Роль связанного с возрастом альфа-синуклеина агрегирования в условной трансгенной модели мыши болезни Паркинсона: последствия для формирования тела Льюи.

Болезнь Паркинсона (PD) — обычное нейродегенеративное расстройство, которое затрагивает все большее число пожилых людей. Несмотря на то, что PD носит в основном спорадический характер, генетические мутации встречаются в группах семей с историей семейной PD (PD). Первая такая мутация, связанная с FPD, вызывает точечную мутацию (A53T) в α-синуклеине (α-син), основном компоненте тел Льюи, которые являются классической патологической отличительной чертой PD. Эти выводы свидетельствуют о том, что α-син является важным фактором развития ДП. В нашем предыдущем исследовании мы разработали аденовальную

Совпадение в аннотации оригинала
Parkinson's disease (PD) is a common neurodegenerative disorder that is affecting an increasing number of older adults. Although PD is mostly sporadic, genetic mutations have been found in cohorts of families with a history of familial PD (FPD). The first such mutation linked to FPD causes a point mutation (A53T) in α-synuclein (α-syn), a major component of …

Oxygen availability influences the incidence of testicular teratoma in Dnd1Ter/+ mice.

Testicular teratomas and teratocarcinomas are the most common testicular germ cell tumors in early childhood and young men, and they are frequently found unilaterally in the left testis. In 129/SvJ mice carrying a heterozygous copy of the potent modifier of tumor incidence Ter, a point mutation in the dead-end homolog one gene (Dnd1 Ter/+), ∼70% of the unilateral teratomas arise in the left testis. We previously showed that in mice, left/right differences in vascular architecture are associated with reduced hemoglobin saturation and increased levels of the hypoxia inducible factor-1 alpha (HIF…

Oesophageal glomus tumours: rare neoplasms with aggressive clinical behaviour.

AIMS: Glomus tumours are neoplasms with perivascular smooth muscle differentiation, which rarely occur in the oesophagus and may behave aggr … rboured NOTCH gene alterations (MIR143::NOTCH2 fusion in two cases; NOTCH3 rearrangement and NOTCH1 point mutation in one case). An ATRX splicing mutation in exon 10 was also identified in one case. CONCLUSION: Oesophageal glomus tumours pose diagnostic challenges, given their rarity at this site, but can be recognised by their characteristic perivascular growt …

Rare and misincorporated DNA N6-methyladenine is a hallmark of cytotoxic stresses for selectively stimulating the stemness and proliferation of glioblastoma cells.

The entity of DNA N6-methyladenine (6mA) in mammals remains elusive and subsequently its roles in diseases are poorly understood. Here we exploited a bacterial DNA contamination-free and ultrasensitive UHPLC-MS/MS assay to reassess DNA 6mA in human glioblastomas and unveiled that DNA 6mA (~0.08 ppm) is extremely rare. By the use of two independent heavy stable isotope-labeling strategies, we further prove that the observed 6mA is solely generated by DNA polymerase-mediated misinocorporation. In vitro experiments point toward that the generation of misincorporated DNA 6mA is associated with the

Nonsense mutation in the novel PERCC1 gene as a genetic cause of congenital diarrhea and enteropathy.

Congenital diarrheas and enteropathies (CODEs) constitute a heterogeneous group of individually rare disorders manifesting with infantile-on … ted patients harboring a shared homozygous variant in PERCC1, comprising the first description of a point mutation in this gene in association with CODE. That both parenteral nutrition dependent children with unexplained diarrhea at our institution harbored a PERCC1 mutation underscores the importance of its inclusion in exome sequencing interpretation.

Baricitinib, a JAK-STAT Inhibitor, Reduces the Cellular Toxicity of the Farnesyltransferase Inhibitor Lonafarnib in Progeria Cells.

Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare multisystem premature aging disorder that leads to early death (mean age of 14.7 years) due to myocardial infarction or stroke. Most cases have a de novo point mutation at position G608G within exon 11 of the LMNA gene. This mutation leads to the production of a permanently farnesylated truncated prelamin A protein called "progerin" that is toxic to the cells. Recently, farnesyltransferase inhibitor (FTI) lonafarnib has been approved by the FDA for the treatment of patients with HGPS. While lonafarnib treatment irrefutably ameliorate…

Complete androgen insensitivity syndrome caused by the c.2678C>T mutation in the androgen receptor gene: A case report.

BACKGROUND: Androgen insensitivity syndrome is an X-linked recessive genetic disease caused by mutations in the androgen receptor gene (AR). However, the underlying molecular mechanisms for the majority of AR variants remain unclear. In this study, we identified a point variant in three patients with complete androgen insensitivity syndrome (CAIS), summarized the correlation analysis, and performed a literature review. CASE SUMMARY: The proband was raised as a girl. In infancy, she was first referred to hospital with a right inguinal hernia. Ultrasonography revealed the absence of a uterus an

Epidemiology and molecular characterization of chikungunya virus from human cases in North India, 2016.

Chikungunya virus (CHIKV), an arthropod-borne Alphavirus is responsible for chikungunya disease. Arthralgia and arthritis are the major symptom. Some patients recover early while others for a very long time. This study provides, epidemiology and molecular characterization of three whole-genome sequences of CHIKV and assessed phylogenetic analysis, physiological properties, antigenicity, and B-cell epitope prediction by in silico. We report the clinical epidemiology of 325 suspected patients. Of these, 118 (36.30%) were confirmed CHIKV positive by either PCR or ELISA. Clinical analysis showed j

Congenital Generalized Lipoatrophy (Berardinelli-Seip Syndrome) Type 1: Description of Novel AGPAT2 Homozygous Variants Showing the Highly Heterogeneous Presentation of the Disease.

Berardinelli-Seip congenital lipoatrophy (BSCL) is characterized by near total fat atrophy, associated with the progressive development of metabolic complications. BSCL type 1 (BSCL1) is caused by mutations in AGPAT2, encoding 1-acylglycerol-3phosphate-O-acyltransferase β (recently renamed lysophosphatidic acid acyltransferase beta), which catalyzes the transformation of lysophosphatidic acid in phosphatidic acid, the precursor of glycerophospholipids and triglycerides. BSCL1 is an autosomal recessive disease due to AGPAT2 pathogenic variants leading to a depletion of triglycerides inside the

A Mutation in VWA1, Encoding von Willebrand Factor A Domain-Containing Protein 1, Is Associated With Hemifacial Microsomia.

BACKGROUND: Hemifacial microsomia (HFM) is a type of rare congenital syndrome caused by developmental disorders of the first and second phar … ce were carried out. RESULTS: Through WES and a set of filtration, we identified a c.G905A:p.R302Q point mutation in a novel candidate pathogenic gene, VWA1. The Phyre2 web portal predicted alterations in secondary and tertiary structures of WARP, indicating changes in its function as well. Predictions of protein-to-protein interactions in five pathways related …

Characterization of two novel Alu element-mediated α-globin gene cluster deletions causing α0-thalassemia by targeted next-generation sequencing.

α-thalassemia is an inherited blood disorder commonly caused by deletions or point mutations involving one or both α-globin genes. Recent studies shed new light on the critical role of upstream enhancers multi-species conserved sequences (MCSs) in the ordered regulation of α-globin gene expression. Herein, we reported two unrelated probands with deletions in α-globin genes and MCSs, respectively. The proband from Family A is a compound heterozygote carrying a known α+ mutation (-α3.7) and a novel 60.2 kb deletion causing the absence of both α-globin genes. The proband from Family B, on the oth…

Therapeutic challenges in a patient with the simple virilizing (SV) form of congenital adrenal hyperplasia (CAH) due to the P30L/I172N genotype.

Background Steroid 21-hydroxylase deficiency is an autosomal recessive disorder, present in 90-95% of all cases with congenital adrenal hype … hydroxyprogesterone (17-OHP). Molecular analysis of the nine most common pseudogene-derived CYP21A2 point mutations was performed in the patient and her family members using the polymerase chain reaction/amplification-created restriction site (PCR/ACRS) method. We detected the P30L/I172N genotype in the patient. She had inherited a mild P30L mutation from her mo …

A Constitutional Activating MET Mutation Makes the Genetic Link between Malignancies and Chronic Inflammatory Diseases.

PURPOSE: The genesis of all cancers results from an accumulation of mutations, constitutional and/or acquired when induced by external mutag … themia vera, and rheumatoid arthritis. We performed genomic analyses for copy number variations and point mutations on laser-microdissected tumor cells from the breast cancer, and on CD34+ cells sorted from bone marrow aspiration, to identify gene abnormalities common to these two types of cell populations. RESULTS: Using ONCOSCAN technology, we identified a co …

AXL Inhibition Extinguishes Primitive JAK2 Mutated Myeloproliferative Neoplasm Progenitor Cells.

Myeloproliferative neoplasms (MPN) are clonal stem cell associated disorders inclusive of chronic myeloid leukemia (CML), Polycythaemia vera (PV), myelofibrosis (MF), and essential thrombocythemia (ET). They are characterized by increased production of myeloid cells with minimal effects on terminal differentiation but can undergo transformation to acute leukemias. PV is the most common chronic myeloproliferative neoplasm and in the majority of cases is characterized by a V617F point mutation in JAK2. This JAK2 activating mutation is also found in about half the patients with MF and ET. Such ab…

Anaplastic astrocytoma cells not detectable on autopsy following long-term temozolomide treatment: A case report.

We herein present an autopsy case of a glioma patient who received long-term treatment with temozolomide (TMZ). The patient, a 35-year-old m … ecimens of the first to the sixth surgeries revealed mutant isocitrate dehydrogenase 1 (IDH1; R132H point mutation) and p53-positive tumor cells, but cells positive for the R132H mutation or p53 could not be detected by immunohistochemistry in the autopsy specimens of the brain after 108 courses of TMZ treatment. Mutant IDH1 (R132H) cells were also not detected …

A Novel Lamin A Mutant Responsible for Congenital Muscular Dystrophy Causes Distinct Abnormalities of the Cell Nucleus.

A-type lamins, the intermediate filament proteins participating in nuclear structure and function, are encoded by LMNA. LMNA mutations can lead to laminopathies such as lipodystrophies, premature aging syndromes (progeria) and muscular dystrophies. Here, we identified a novel heterozygous LMNA p.R388P de novo mutation in a patient with a non-previously described severe phenotype comprising congenital muscular dystrophy (L-CMD) and lipodystrophy. In culture, the patient's skin fibroblasts entered prematurely into senescence, and some nuclei showed a lamina honeycomb pattern. C2C12 myoblasts wer

Deletion at the GCNT2 Locus Causes Autosomal Recessive Congenital Cataracts.

PURPOSE: The aim of this study is to identify the molecular basis of autosomal recessive congenital cataracts (arCC) in a large consanguineous pedigree. METHODS: All participating individuals underwent a detailed ophthalmic examination. Each patient's medical history, particularly of cataracts and other ocular abnormalities, was compiled from available medical records and interviews with family elders. Blood samples were donated by all participating family members and used to extract genomic DNA. Genetic analysis was performed to rule out linkage to known arCC loci and genes. Whole-exome sequ

Clinical, hormonal, ovarian, and genetic aspects of 46,XX patients with congenital adrenal hyperplasia due to CYP17A1 defects.

OBJECTIVE: To perform a clinical, biochemical, and molecular evaluation of patients with CYP17A1 defects, including ovarian imaging. DESIGN: Retrospective study. SETTING: Tertiary care center. PATIENT(S): Sixteen patients with congenital adrenal hyperplasia due to CYP17A1 defects with a median chronological age of 20 years and belonging to 10 unrelated families. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Clinical and biochemical parameters, molecular diagnosis, ovarian imaging, and therapeutic management. RESULT(S): Seventy-one percent of patients presented with primary amenorrhea,

Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia.

With intensified pediatric-like therapy and genetic disease dissection, the field of adult acute lymphoblastic leukemia (ALL) has evolved recently. In this new context, we aimed to reassess the value of conventional risk factors with regard to new genetic alterations and early response to therapy, as assessed by immunoglobulin/T-cell receptor minimal residual disease (MRD) levels. The study was performed in 423 younger adults with Philadelphia chromosome-negative ALL in first remission (265 B-cell precursor [BCP] and 158 T-cell ALL), with cumulative incidence of relapse (CIR) as the primary en