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Evidence for the involvement of a hematopoietic progenitor cell in systemic mastocytosis from single-cell analysis of mutations in the c-kit gene.

Mast cells are derived from multipotential hematopoietic progenitors and are clonally increased in systemic mastocytosis, a disease associated with point mutations of codon 816 (most commonly Asp816Val) of c-kit. To study the lineage relationship and the extent of expansion of cells derived from the mutated clone, we examined the occurrence of the Asp816Val c-kit mutation in genomic DNA of individual sorted peripheral blood T cells, B cells, and monocytes in patients with indolent systemic mastocytosis. The mutation was detected in varying frequencies in the genomic DNA of individual B cells a…

A fluorogenic allele-specific amplification method for DNA-based screening for inherited metabolic disorders.

Rapidly growing mutation databases for various inherited metabolic diseases raise the possibility of neonatal screening by DNA-based diagnosis. It is therefore important to develop a simple DNA diagnostic method which is suitable for processing a large number of samples. We have devised an allele-specific amplification (ASA) method with a fluorogenic probe (TaqMan probe) to detect point mutations. A pairwise PCR amplification with two sets of allele-specific primers was performed in the presence of the TaqMan probe with real-time fluorescence monitoring on an ABI PRISM 7700 sequence detector. …

[Brain stem ischemia in a boy with resistance to C activated protein and elevated lipoprotein A].

INTRODUCTION: Activated protein C resistance is the most common hereditary coagulation abnormality. In the majority of cases it results from a point mutation Arg506-->Gln of the factor V gene, and characterized by a poor anticoagulant response to activated protein C. CLINICAL CASE: We report the clinical case of a 6-year-old obese boy, who presented with acute hemiparesis. A cerebral MRI revealed an area of infarction in the left hemiprotuberance. Further investigation identified activated protein C resistance (heterozygosity for factor V Leiden) and elevation in lipoprotein (a). His mother a…

Four new cases of lethal osteogenesis imperfecta due to glycine substitutions in COL1A1 and genes. Mutations in brief no. 152. Online.

Perinatal lethal osteogenesis imperfecta is the result of heterozygous mutations of the COL1A1 and COL1A2 genes. Here we describe the molecu … transitions in COL1A1(cases 1,2), to a G-->T transversion in COL1A2 (case 3), and to two contiguous point mutations in COL1A2 (case 4). All five nucleotide changes appeared to be fresh mutations. COLIA1(accession number Z74615) and COL1A2(accession number Z74616) wild type coding sequences (cDNA) were deduced from the EMBL DNA sequence database. The mutations de …

The molecular basis of X-linked deafness type 3 (DFN3) in two sporadic cases: identification of a somatic mosaicism for a POU3F4 missense mutation.

We have investigated two unrelated males with X-linked deafness type 3 (DFN3) for mutations in the POU3F4 gene. In one patient, we observed … in the POU homeodomain and are predicted to disrupt the DNA binding of the POU3F4 protein. All nine point mutations thus far described were found in the POU domains of POU3F4. Since these domains constitute only 35% of the open reading frame of POU3F4, there is a statistically significant preference for mutations in the POU-specific and POU homeodomain.

Identification of a single base change in a new human mutant glucose-6-phosphate dehydrogenase gene by polymerase-chain-reaction amplification of the entire coding region from genomic DNA.

We report the characterization at the molecular level of a mutant glucose-6-phosphate dehydrogenase (G6PD) gene in a Greek boy who presented … r, who was found to be heterozygous for the new BalI site. This is the first transversion among the point mutations thus far reported in the human G6PD gene.

[Analysis of the content of some chemical trace elements in intact tooth enamel of individuals with different frequency of polymorphisms of the kallikrein-4 gene].

UNLABELLED: The aim the study. Assessment of the content of various trace elements in the intact tooth enamel of individuals genotyped by polymorphism G/G, G/A, A/A of the kallikrein-4 gene at mutational points G2664153A and G2142A. MATERIAL AND METHODS: Laboratory examination of 160 enamel samples of intact premolars of the upper jaws removed according to orthodontic indications in individuals with different genotypes of G/G, G/A and A/A of the kallikrein-4 gene at mutation points G2664153A and G2142A was carried out using X-ray spectral fluorescence analysis. RESULTS: In the intact tooth e

Diagnostic approach to the hyper-IgE syndromes: immunologic and clinical key findings to differentiate hyper-IgE syndromes from atopic dermatitis.

BACKGROUND: Hyper-IgE syndromes (HIES) are primary immunodeficiency disorders characterized by Staphylococcus aureus abscesses, recurrent pneumonia, increased serum IgE levels, and eczema. The association of heterozygous signal transducer and activator of transcription 3 (STAT3) mutations with autosomal dominant (AD)-HIES allows the differentiation of AD-HIES from disorders associated with eczema and increased serum IgE levels, such as other primary immunodeficiencies and atopic dermatitis. OBJECTIVE: To facilitate early diagnosis of AD-HIES to initiate appropriate therapy. METHODS: The clin

Structural insights on perlecan and Schwartz-Jampel syndrome.

Perlecan is an essential multi-domain, disulfide bond rich basement membrane protein. Mutations in perlecan cause Schwartz-Jampel syndrome and dyssegmental dysplasia. While there has been a large body of experimental work reported on perlecan, there is only minimal structural information available to date. There is no prior structural data for region 3 of perlecan in which some Schwartz-Jampel syndrome causing point mutations have been reported. Here, we produce constructs of the disulfide rich region 3 of perlecan along with five mutations previously reported to cause Schwatz-Jampel syndrome.…

Spinocerebellar ataxias: from pathogenesis to recent therapeutic advances.

Spinocerebellar ataxia is a phenotypically and genetically heterogeneous group of autosomal dominant-inherited degenerative disorders. The gene mutation spectrum includes dynamic expansions, point mutations, duplications, insertions, and deletions of varying lengths. Dynamic expansion is the most common form of mutation. Mutations often result in indistinguishable clinical phenotypes, thus requiring validation using multiple genetic testing techniques. Depending on the type of mutation, the pathogenesis may involve proteotoxicity, RNA toxicity, or protein loss-of-function. All of which may dis…

Novel HSPG2 Gene Mutation Causing Schwartz-Jampel Syndrome in a Moroccan Family: A Literature Review.

Schwartz-Jampel syndrome type 1 (SJS1) is a rare autosomal recessive musculoskeletal disorder caused by various mutations in the HSPG2 gene encoding the protein perlecan, a major component of basement membranes. We report a novel splice mutation HSPG2(NM_005529.7):c.3888 + 1G > A and a known point mutation HSPG2(NM_005529.7):c.8464G > A, leading to the skipping of exon 31 and 64 in mRNA, respectively, in a Moroccan child with clinical features suggestive of SJS1 and carrying two compound heterozygous mutations in the HSPG2 gene detected by next-generation sequencing. Both parents harboured one…

Prime editing optimized RTT permits the correction of the c.8713C>T mutation in DMD gene.

Duchenne muscular dystrophy is a severe debilitating genetic disease caused by different mutations in the DMD gene leading to the absence of … t in the myotubes that they formed. RTT optimization permitted us to improve the prime editing of a point mutation located at +13 nucleotides from the nick site to restore dystrophin protein.

Gain-of-Function Mutations R249C and S250C in Complement C2 Protein Increase C3 Deposition in the Presence of C-Reactive Protein.

The impairment of the alternative complement pathway contributes to rare kidney diseases such as atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G). We recently described an aHUS patient carrying an exceptional gain-of-function (GoF) mutation (S250C) in the classical complement pathway component C2 leading to the formation of hyperactive classical convertases. We now report the identification of the same mutation and another C2 GoF mutation R249C in two other patients with a glomerulopathy of uncertain etiology. Both mutations stabilize the classical C3 convertases by a simi

Усиленный цитопатический эффект японского энцефалита штамма SA14-14-2: вероятное объединение мутации в аминокислоте его белка.

Японский энцефалит (JE) — вирусная болезнь, переносимая комарами. Это проблема здравоохранения во всем мире, поскольку она вызывает острый синдром энцефалита (AES). Согласно сообщениям, большое число случаев заболевания ДЖ/АЭС происходит в районах, где осуществляется или разрабатывается программа вакцинации ДЖ. Важную роль, возможно, играют частичный охват вакцинами и появление новых вариантов японского энцефалитного вируса (JEV). Белок конверта (E) JEV является одним из основных антигенных определяющих факторов и несет ответственность за иммуногенные реакции, а также за синтез мембраны и вири

Совпадение в аннотации оригинала
Japanese encephalitis (JE) is a mosquito-borne viral disease. It is a global public health concern since it causes an acute encephalitis syn … uence analysis of the E protein gene of the cell-culture adapted vaccine strain showed an important point mutation. The mutation in the E protein gene was identical to its wild-type parent strain SA14. This study suggests the possibility of reversion mutation and exaltation of vaccine strains following adaptation in the host cells.

Use of molecular dynamics simulation to explore structural facets of human prion protein with pathogenic mutations.

Prion diseases are caused by mutations at different positions of the prion protein. A large number of pathogenic mutations are reported in the literature. Two of such point mutations T193I and R148H located at two different helical strands (H2 and H1) of the prion protein associated with fCJD (familial Creutzfeld-Jacob disease) are studied. We have used classical molecular dynamics (MD) simulation technique to understand the conformational changes and dynamics of the protein under the effect of mutation and compared with the native prion protein. The results indicate that: both mutated forms a…

PU.1 downregulation in murine radiation-induced acute myeloid leukaemia (AML): from molecular mechanism to human AML.

The transcription factor PU.1, encoded by the murine Sfpi1 gene (SPI1 in humans), is a member of the Ets transcription factor family and plays a vital role in commitment and maturation of the myeloid and lymphoid lineages. Murine studies directly link primary acute myeloid leukaemia (AML) and decreased PU.1 expression in specifically modified strains. Similarly, a radiation-induced chromosome 2 deletion and subsequent Sfpi1 point mutation in the remaining allele lead to murine radiation-induced AML. Consistent with murine data, heterozygous deletion of the SPI1 locus and mutation of the -14kb …

Pathogenic mitochondrial mt-tRNA(Ala) variants are uniquely associated with isolated myopathy.

Pathogenic mitochondrial DNA (mtDNA) point mutations are associated with a wide range of clinical phenotypes, often involving multiple organ systems. We report two patients with isolated myopathy owing to novel mt-tRNA(Ala) variants. Muscle biopsy revealed extensive histopathological findings including cytochrome c oxidase (COX)-deficient fibres. Pyrosequencing confirmed mtDNA heteroplasmy for both mutations (m.5631G>A and m.5610G>A) whilst single-muscle fibre segregation studies (revealing statistically significant higher mutation loads in COX-deficient fibres than in COX-positive fibres), hi…

Atypical Presentation for Friedreich Ataxia in a Child.

The classic phenotype of Friedreich ataxia is characterized by dysarthria, progressive limb and trunk ataxia, loss of reflexes, and gait disturbance with the onset of disease before the second decade. Homozygous trinucleotide repeat expansion of GAA in the FXN gene is found in 98% of patients. Two-5% of all patients have a repeat expansion on one allele and a point mutation on the other allele. Atypical phenotype is found in 25% of patients. A 10-year-old boy presented with congenital biliary atresia and progressive gait abnormality. His examination was significant for spastic gait, hyperrefle…

The C175R mutation alters nuclear localization and transcriptional activity of the nephronophthisis NPHP7 gene product.

Nephronophthisis (NPH) is a rare autosomal ciliopathy, but the leading cause for hereditary end-stage renal disease in children. Most NPH fa … tions have been identified so far. We describe here that the recently identified GLIS2/NPHP7(C175R) point mutation abolished the nuclear localization of GLIS2/NPHP7. Forced nuclear import did not rescue the transcriptional defects of GLIS2/NPHP7(C175R), indicating additional defects as DNA-binding protein. We further observed that wild type, but not GLIS2/NPHP7( …

Renal involvement in MELAS syndrome - a series of 5 cases and review of the literature.

Renal dysfunction is increasingly recognized as a potential clinical feature of mitochondrial cytopathies such as mitochondrial encephalomyo … ith the typical symptoms of MELAS syndrome, genetic testing in these patients identified the A3243G point mutation in the tRNALeu gene of the mitochondrial DNA (mtDNA). The diagnosis of MELAS syndrome was thus considered to be unequivocal. The incidence of kidney disease in MELAS syndrome may be underestimated although a study is required to investigate this hyp …