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Constitutional and mosaic large NF1 gene deletions in neurofibromatosis type 1. 总被引:7,自引:1,他引:7
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S A Rasmussen S D Colman V T Ho C R Abernathy P H Arn L Weiss C Schwartz R A Saul M R Wallace 《Journal of medical genetics》1998,35(6):468-471
A set of neurofibromatosis type 1 (NF1) patients was screened for large NF1 gene deletions by comparing patient and parent genotypes at 10 intragenic polymorphic loci. Of 67 patient/parent sets (47 new mutation patients and 20 familial cases), five (7.5%) showed loss of heterozygosity (LOH), indicative of NF1 gene deletion. These five patients did not have severe NF1 manifestations, mental retardation, or dysmorphic features, in contrast to previous reports of large NF1 deletions. All five deletions were de novo and occurred on the maternal chromosome. However, two patients showed partial LOH, consistent with somatic mosaicism for the deletion, suggesting that mosaicism may be more frequent in NF1 than previously recognised (and may have bearing on clinical severity). We suggest that large NF1 deletions (1) are not always associated with unusual clinical features, (2) tend to occur more frequently on maternal alleles, and (3) are an important mechanism for constitutional and somatic mutations in NF1 patients. 相似文献
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Baser ME Kuramoto L Woods R Joe H Friedman JM Wallace AJ Ramsden RT Olschwang S Bijlsma E Kalamarides M Papi L Kato R Carroll J Lázaro C Joncourt F Parry DM Rouleau GA Evans DG 《Journal of medical genetics》2005,42(7):540-546
Neurofibromatosis 2 (NF2) patients with constitutional splice site NF2 mutations have greater variability in disease severity than NF2 patients with other types of mutations; the cause of this variability is unknown. We evaluated genotype-phenotype correlations, with particular focus on the location of splice site mutations, using mutation and clinical information on 831 patients from 528 NF2 families with identified constitutional NF2 mutations. The clinical characteristics examined were age at onset of symptoms of NF2 and number of intracranial meningiomas, which are the primary indices of the severity of NF2. Two regression models were used to analyse genotype-phenotype correlations. People with splice site mutations in exons 1–5 had more severe disease than those with splice site mutations in exons 11–15. This result is compatible with studies showing that exons 2 and 3 are required for self-association of the amino terminal of the NF2 protein in vitro, and that deletions of exons 2 and 3 in transgenic and knockout mouse models of NF2 cause a high prevalence of Schwann cell derived tumours. 相似文献
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Barrowman J Wiley PA Hudon-Miller SE Hrycyna CA Michaelis S 《Human molecular genetics》2012,21(18):4084-4093
The zinc metalloprotease ZMPSTE24 plays a critical role in nuclear lamin biology by cleaving the prenylated and carboxylmethylated 15-amino acid tail from the C-terminus of prelamin A to yield mature lamin A. A defect in this proteolytic event, caused by a mutation in the lamin A gene (LMNA) that eliminates the ZMPSTE24 cleavage site, underlies the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS). Likewise, mutations in the ZMPSTE24 gene that result in decreased enzyme function cause a spectrum of diseases that share certain features of premature aging. Twenty human ZMPSTE24 alleles have been identified that are associated with three disease categories of increasing severity: mandibuloacral dysplasia type B (MAD-B), severe progeria (atypical 'HGPS') and restrictive dermopathy (RD). To determine whether a correlation exists between decreasing ZMPSTE24 protease activity and increasing disease severity, we expressed mutant alleles of ZMPSTE24 in yeast and optimized in vivo yeast mating assays to directly compare the activity of alleles associated with each disease category. We also measured the activity of yeast crude membranes containing the ZMPSTE24 mutant proteins in vitro. We determined that, in general, the residual activity of ZMPSTE24 patient alleles correlates with disease severity. Complete loss-of-function alleles are associated with RD, whereas retention of partial, measureable activity results in MAD-B or severe progeria. Importantly, our assays can discriminate small differences in activity among the mutants, confirming that the methods presented here will be useful for characterizing any new ZMPSTE24 mutations that are discovered. 相似文献
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Naturally occurring utrophin correlates with disease severity in Duchenne muscular dystrophy 总被引:1,自引:0,他引:1
Kleopa KA Drousiotou A Mavrikiou E Ormiston A Kyriakides T 《Human molecular genetics》2006,15(10):1623-1628
Although there is good experimental data that utrophin, the autosomal analog of dystrophin, can ameliorate the phenotype in dystrophinopathies, there is scant evidence from human data to support this hypothesis. We investigated in diagnostic muscle biopsies from 16 patients with Duchenne muscular dystrophy (DMD) the level of utrophin expression using quantitative immunoblot analysis. In 13 of 16 patients, in whom there was adequate follow-up data, utrophin expression was correlated to two clinical endpoints: age at reaching Hammersmith score of 30/40 and age at becoming wheelchair-bound. We found that utrophin expression increases with age in DMD and that there is a significant positive correlation between the quantity of utrophin at initial biopsy and time to becoming wheelchair-bound. 相似文献
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ObjectiveIn a cross sectional study, we investigated the relationships between knee pain and mechanical loading across the knee, as indicated by the external knee adduction moment (KAM) during walking in patients with symptomatic knee OA who were distinguished by different radiographic disease severities.MethodsData from 137 symptomatic medial knee OA patients were used. Based on Kellgren/Lawrence (K/L) grading, the patients were divided into radiographically less severe (K/L ≤ 2, n = 68) or severe (K/L > 2, n = 69) medial knee OA. Overall knee pain was rated on a 10 cm visual analog scale, and peak KAM and KAM impulses were obtained from gait analyses. Mixed linear regression analyses were performed with KAM variables as the outcome, and pain and disease severity as independent variables, adjusting for age, gender, and walking speed.ResultsIn adjusted analyses, less severe patients demonstrated negative relationships between pain intensities and dynamic loading. The severe patient group showed no relationship between pain intensity and peak KAM, and a positive relationship between pain intensity and KAM impulse.ConclusionIn radiographically less severe knee OA, the negative relationships between pain intensity and dynamic knee joint loading indicate a natural reaction to pain, which will limit the stress on the joint. In contrast, either absent or positive relationships between pain and dynamic loading in severe OA may lead to overuse and accelerated disease progression. These findings may have a large potential interest for strategies of treatment in knee OA. 相似文献
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A. Therrien L. Chapuy M. Bsat M. Rubio G. Bernard E. Arslanian K. Orlicka A. Weber B.-P. Panzini J. Dorais E.-J. Bernard G. Soucy M. Bouin M. Sarfati 《Clinical and experimental immunology》2019,195(2):251-264
Neutrophils are detected in inflamed colon in Crohn’s disease (CD). However, whether the frequency and/or activation of circulating or gut tissue neutrophils correlate with endoscopic severity remains to be investigated. A cohort of 73 CD patients was prospectively enrolled according to endoscopic severity and treatment history. Individuals with active disease were stratified using the Montreal classification. Harvey–Bradshaw Index (HBI) and Simple Endoscopic Score for Crohn’s Disease (SES-CD) were performed at the time of ileocolonoscopy. Frequency of neutrophils and their expression of CD66b and CD64 were assessed in paired blood and colonic biopsies using flow cytometry. The percentage of neutrophils increased in inflamed colon and correlated with SES-CD in the entire cohort of patients examined, as well as in the subgroup with inflammatory (B1) active disease. SES-CD further correlated with neutrophil CD66b expression in mucosa but not blood and, conversely, with neutrophil CD64 expression in blood but not mucosa. However, the evaluation of neutrophil activation in mucosa when compared to blood reflected disease activity more clearly. Finally, a neutrophil activation power index (CD66b in mucosa X CD64 in blood) that correlated with SES-CD discriminated between patients with mild and severe disease. In conclusion, the frequency and activation of colonic neutrophils correlated with SES-CD, highlighting that mucosal neutrophils are associated with disease severity in CD. 相似文献
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Tombolan L Orso F Guzzardo V Casara S Zin A Bonora M Romualdi C Giorgi C Bisogno G Alaggio R Pinton P De Pittà C Taverna D Rosolen A Lanfranchi G 《The American journal of pathology》2011,179(5):2611-2624
Rhabdomyosarcoma (RMS) is the most common childhood sarcoma and is identified as either the embryonal or alveolar (ARMS) subtype. In approximately 75% of cases, ARMSs are characterized by specific chromosomal translocations that involve PAX and FKHR genes. ARMS gene expression signatures vary, depending on the presence or absence of the translocations. Insulin-like growth factor-binding protein 2 (IGFBP2) is strongly overexpressed in translocation-negative RMS. Because IGFBP2 is associated with tumorigenesis, we investigated its functional role in RMS. An analysis of IGFBP2 distribution in RMS cell lines revealed a strong accumulation in the Golgi complex, in which morphological characteristics appeared peculiarly modified. After silencing IGFBP2 expression, our microarray analysis revealed mostly cell cycle and actin cytoskeleton gene modulations. In parallel, IGFBP2-silenced cells showed reduced cell cycle and rates of invasion and decreased seeding in the lungs after tail vein injections in immunodeficient mice. An analysis of IGFBP2 mRNA and protein localization in human tumors showed abnormal protein accumulation in the Golgi complex, mostly in PAX/FKHR-negative RMS. Moreover, an analysis of patients with RMS revealed the presence of conspicuous circulating levels of IGFBP2 proteins in children with highly aggressive RMS tumors. Taken together, our data provide evidence that IGFBP2 contributes to tumor progression and that it could be used as a marker to better classify clinical and biological risks in RMS. 相似文献
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Serum albumin level correlates with disease severity in patients with Hemorrhagic Fever with Renal Syndrome 总被引:1,自引:0,他引:1
Kim YO Yoon SA Ku YM Yang CW Kim YS Kim SY Choi EJ Chang YS Bang BK 《Journal of Korean medical science》2003,18(5):696-700
Hypoalbuminemia frequently occurs in Hemorrhagic Fever with Renal Syndrome (HFRS), but clinical significance of hypoalbuminemia is not well known. This study was designed to evaluate hypoalbuminemia as a marker of severity of disease in patients with HFRS. We evaluated the relationship between the level of serum albumin and clinical parameters representing the severity of disease in 144 patients with HFRS. The patients were divided into three groups based on the level of serum albumin; Group I (normal serum albumin), Group II (serum albumin <3.5 g/dL and >/=3.0 g/dL), and Group III (serum albumin <3.0 g/dL). Of the total of 144 patients, 42 patients (29.2%) were categorized as Group I, 39 patients (27.1%) as Group II, and 63 patients (43.8%) as Group III. Group III had a higher rate of incidence in episode of hypotension, pulmonary edema than did Group I and Group II. The lowest level of serum albumin was positively correlated with platelet count (r=0.505, p<0.001) and was negatively correlated with leukocyte count (r=-0.329, p<0.001), BUN (r=-0.484, p<0.001), serum creatinine (r=-0.394, p<0.001), and AST (r=-0.251, p=0.002). Our data suggest that hypoalbuminemia frequently occurs in the acute stage of HFRS, and level of serum albumin is associated with the disease severity of HFRS. 相似文献
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Matsushita Y Furukawa T Kasanuki H Nishibatake M Kurihara Y Ikeda A Kamatani N Takeshima H Matsuoka R 《Journal of human genetics》2007,52(6):543-548
Junctophilin subtypes, designated as JPH1∼4, are protein components of junctional complexes and play essential roles in cellular
Ca2+ signaling in excitable cells. Knockout mice lacking the cardiac-type Jph2 die of embryonic cardiac arrest, and the mutant cardiac myocytes exhibit impaired formation of peripheral couplings and arrhythmic
Ca2+ signaling caused by functional uncoupling between dihydropyridine and ryanodine receptor channels. Based on these observations,
we hypothesized that mutations of JPH2 could cause human genetic cardiac diseases. Among 195 Japanese patients (148 index cases and 47 affected family members)
with hypertrophic cardiomyopathy (HCM), two heterozygous nonsynonymous nucleotide transitions, G505S and R436C, were newly
found in JPH2. When Fisher’s exact test was used to compare index cases with HCM to unrelated Japanese healthy controls in the frequencies
of mutant alleles, only the G505S mutation showed statistical significance (4/296 HCM patients and 0/472 control individuals,
P=0.022). This result was still significant after Bonferroni’s correction for multiple comparisons (P=0.044). To the best of our knowledge, this is the first report on JPH2 mutation associated with HCM. 相似文献
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《Genetics in medicine》2010,12(1):44-51
PurposeA validated disease severity scoring system (DS3) for Gaucher disease type 1 (GD1) is needed to standardize patient monitoring and to define patient cohorts in clinical studies.MethodsDS3 domains were established by an expert physician group using the nominal group technique of consensus formation. Items were selected by 36 GD1 physicians. The expert group determined appropriate measurement techniques for each item. Measurements were weighted considering contributions to GD1 morbidity and mortality. Consensus Clinical Global Impression Severity scores for sample cases were compared with average DS3 scores. A minimal clinically important difference in GD1 DS3 score was calculated.ResultsThe GD1 DS3 includes bone (42% of score), hematologic (32%), and visceral domains (26%); individual items use routine assessments, including medical history, blood chemistry, organ volume measurements, and bone evaluations (magnetic resonance imaging and dual x-ray absorptiometry). The maximum score is 19. Interrater reliability was 0.97 (Cohen's kappa). DS3 scores were highly correlated with Clinical Global Impression Severity scores (r2 = 0.89). The minimal clinically important difference was −3.2 improvement and +3.9 deterioration.ConclusionThis DS3 accurately quantifies GD1 status and intrapatient change over time. Testing of reliability and validity will continue to allow eventual implementation of the DS3 in clinical studies and routine practice. 相似文献
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《European journal of medical genetics》2017,60(2):93-99
Neurofibromatosis type 1 (NF1) is caused by mutations of the NF1 gene and is one of the most common human autosomal dominant disorders. The patient shows different signs on the skin and other organs from early childhood. The best known are six or more café au lait spots, axillary or inguinal freckling, increased risk of developing benign nerve sheath tumours and plexiform neurofibromas. Mutation detection is complex, due to the large gene size, the large variety of mutations and the presence of pseudogenes. Using Ion Torrent PGM™ Platform, 73 mutations were identified in 79 NF1 Italian patients, 51% of which turned out to be novel mutations. Pathogenic status of each variant was classified using “American College of Medical Genetics and Genomics” guidelines criteria, thus enabling the classification of 96% of the variants identified as being pathogenic. The use of Next Generation Sequencing has proven to be effective as for costs, and time for analysis, and it allowed us to identify a patient with NF1 mosaicism. Furthermore, we designed a new approach aimed to quantify the mosaicism percentage using electropherogram of capillary electrophoresis performed on Sanger method. 相似文献
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Seroreactivity to Chlamydia trachomatis Hsp10 correlates with severity of human genital tract disease 总被引:4,自引:0,他引:4
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LaVerda D Albanese LN Ruther PE Morrison SG Morrison RP Ault KA Byrne GI 《Infection and immunity》2000,68(1):303-309
We have identified the chlamydial heat shock protein Hsp10 as a potential correlate to the immunopathogenic process in women with tubal factor infertility (TFI). The human serologic response to chlamydial Hsp10, Hsp60, and major outer membrane protein (MOMP) was measured by enzyme-linked immunosorbent assay. Three populations of women were studied: uninfected controls (CU), acutely infected (AI) women, and women with TFI. Sera from women in the AI and TFI groups both recognized Hsp10 more frequently and at a higher overall level than sera from healthy uninfected controls. Moreover, the infertile women had significantly greater Hsp10 seroreactivity than acutely infected women, indicating a concomitant increase of Hsp10 recognition in populations with increasing levels of disease severity. Hsp60 reactivity showed a similar correlation in these populations, while MOMP reactivity peaked at the same level in both AI and TFI populations but did not increase with disease severity. Test populations were standardized by level of reactivity to formalin-fixed Chlamydia trachomatis elementary bodies (EBs) to address whether these associations were reflections of increased overall chlamydial exposure rather than a property specific to Hsp10. Associations between Hsp10 seropositivity and TFI were greater in the EB(+) subgroup while associations among the EB(-) subgroup were diminished. When restricted to the EB(+) subgroups, Hsp60 and MOMP responses in the TFI population did not increase significantly over the level of AI group responses. Thus, among women with similar exposure to chlamydiae, the serologic response to Hsp10 exhibited a stronger correlation with TFI than did the response to Hsp60 or MOMP. These findings support the hypothesis that the serological response to C. trachomatis heat shock proteins is associated with the severity of disease and identifies Hsp10 as an antigen recognized by a significant proportion of women with TFI. 相似文献
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Genetic analysis of determinants of disease severity and virus concentration in cauliflower mosaic virus 总被引:1,自引:0,他引:1
Cauliflower mosaic virus (CaMV) strains CM1841 and W260 produced markedly different symptoms when inoculated onto turnips (Brassica campestris L. 'Just Right'). The CM1841 strain induced a mild degree of stunting of infected plants while strain W260 caused moderate to severe stunting. Although CM1841 was significantly milder than W260, it accumulated to a significantly higher concentration than W260 in systemically infected leaves. We constructed a series of hybrid viruses in order to map regions of W260 responsible for enhanced disease severity relative to CM1841 and to map regions of CM1841 responsible for higher virus accumulation. We found that the characteristic degree of stunting caused by a CaMV isolate is determined in a complex manner by viral genes that influence viral gene expression and viral genes that disrupt host metabolism. Genes I and VI influenced both virus concentration and stunting severity, suggesting that these regions affected disease severity primarily through their effect on gene expression. In addition, an interaction between genes IV and VI was observed which further indicated that stunting severity was influenced by differential accumulation of virus. In contrast, three regions of W260 influenced the stunting phenotype but had no effect, or a negative effect, on virus concentration. The three regions contained (1) portions of genes II and III, (2) gene IV, independent of gene VI, and (3) the 3' half of gene V and the 19 S promoter. These regions may influence stunting severity primarily by disrupting host metabolism. Additionally, some of the chimeric viruses induced systemic necrosis on leaves, a symptom that is not characteristic of either CM1841 or W260. The necrotic flecking symptom was caused by an interaction between a W260 DNA segment containing gene I and the 5' half of gene II and a CM1841 DNA segment containing the 3' half of gene II, gene III, and gene IV. 相似文献
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Zsuzsanna Kelemen Dumitru Moldovan Enikő Mihály Beáta Visy Gábor Széplaki Dorottya Csuka George Füst Henriette Farkas Lilian Varga 《Clinical immunology (Orlando, Fla.)》2010,134(3):354-358
The diagnosis of hereditary angioedema (HAE) is based on complement tests. We studied for the first time the possible association between complement parameters measured at the time of diagnosis and disease severity in 115 patients with HAE.Serum levels of functional C1-inhibitor (C1-INHf), antigenic C1-inhibitor (C1-INHa), C4 and hemolytic activity of the classical pathway (CH50) were determined at the time of diagnosis. We found a significant correlation between severity scores and baseline C1-INHf levels, as determined by ELISA assay (p = 0.0003). On the other hand, there was no correlation between severity scores and other complement parameters (C1-INHa, C4, and CH50).We consider the correlation between severity scores and baseline C1-INHf levels an important pathophysiological observation. Our findings underlie the potential significance of monitoring functional C1-INH levels in relation to clinical disease course. 相似文献
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Forstmeyer D Henke-Gendo C Bröcker V Wildner O Heim A 《Journal of medical virology》2008,80(2):294-297
Disseminated adenovirus (HAdV) infections are serious complications in allogenic stem cell transplant (SCT) recipients. Quantitative HAdV DNA detection in blood samples demonstrated the association of high virus loads with disease and improved early diagnosis. However, the pathogenesis of disseminated HAdV disease, for example sources of HAdV DNA shedding in the blood stream and association of HAdV replication sites with disease manifestations, remained obscure. In this report, 24 bioptic and autoptic organ and tissue samples of an adult SCT recipient suffering from disseminated infection were quantitatively analyzed for HAdV DNA. Results indicate subsequent virus replication in the colon, bone marrow and liver as origin of HAdV DNAemia, which increased from 1.4 x 10(4) copies/ml to a peak of 2 x 10(9) copies/ml over a period of 84 days in spite of antiviral therapy. Symptoms as diarrhoea, bone marrow failure and hepatic failure were clearly linked to high HAdV DNA concentrations in affected organs. For example, the HAdV DNA level was 2.2 x 10(3) copies/cell in a colon biopsy when the patient suffered from diarrhoea whereas only 1.1 x 10(1) copies/cell were detected when symptoms had improved. Focal HAdV infection of the liver as demonstrated by laser microdissection was followed by fulminant virus replication with 1.3 x 10(5) copies of HAdV DNA/cell causing terminal hepatic failure. In conclusion, pathogenesis of disseminated HAdV disease was associated with virus replication in affected organs and not immune mediated as suggested recently by a fatal case of gene therapy with a non-replication competent HAdV-C5 vector. 相似文献