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1.
Genetic and mutational heterogeneity of autosomal recessive chronic granulomatous disease in Tunisia
El Kares R Barbouche MR Elloumi-Zghal H Bejaoui M Chemli J Mellouli F Tebib N Abdelmoula MS Boukthir S Fitouri Z M'Rad S Bouslama K Touiri H Abdelhak S Dellagi MK 《Journal of human genetics》2006,51(10):887-895
NADPH oxidase, a multi-subunit protein consisting of cytosolic components and the membrane-bound heterodimer, plays an instrumental role in host defence mechanisms of phagocytes. Genetic deficiency of the enzymatic complex results in an inherited disorder, chronic granulomatous disease (CGD), which is characterized by an impaired phagocyte microbicidal activity. X-Linked (XL) CGD results from a mutation in the CYBB gene encoding the gp91phox subunit, while autosomal recessive (AR) CGD is associated with mutations in one of the NCF1, NCF2 and CYBA genes that encode the p47phox, p67phox and p22phox subunits, respectively. In the study reported here, we investigated genetic defects underlying CGD in 15 Tunisian patients from 14 unrelated families. Haplotype analyses and homozygosity mapping with microsatellite markers around known CGD genes assigned the genetic defect to NCF1 in four patients, to NCF2 in four patients and to CYBA in two patients. However, one family with two CGD patients seemed not to link the genetic defect to any known AR-CGD genes. Mutation screening identified two novel mutations in NCF2 and CYBA in addition to the recurrent mutation, ΔGT, in NCF1 and a splice site mutation previously reported in a North African patient. Our results revealed the genetic and mutational heterogeneity of the AR recessive form of CGD in Tunisia. 相似文献
2.
Fattahi F Badalzadeh M Sedighipour L Movahedi M Fazlollahi MR Mansouri SD Khotaei GT Bemanian MH Behmanesh F Hamidieh AA Bazargan N Mamishi S Zandieh F Chavoshzadeh Z Mohammadzadeh I Mahdaviani SA Tabatabaei SA Kalantari N Tajik S Maddah M Pourpak Z Moin M 《Journal of clinical immunology》2011,31(5):792-801
Background
Chronic granulomatous disease (CGD) is a rare immunodeficiency due to a genetic defect in one of the NADPH-oxidase components. We studied CGD inheritance forms (autosomal recessive (AR) or X-linked (XL)) and AR-CGD subtypes in Iran.Methods
Clinical and functional investigations were conducted in 93 Iranian CGD patients from 75 families.Results
Most of the patients were AR-CGD (87.1%). This was related to consanguineous marriages (p?=?0.001). The age of onset of symptoms and diagnosis were lower in XL-CGD compared with AR-CGD (p?0.0001 for both). Among AR-CGD patients, p47phox defect was the predominant subtype (55.5%). The most common clinical features in patients were lymphadenopathy (65.6%) and pulmonary involvement (57%). XL-CGD patients were affected more frequently with severe infectious manifestations.Conclusions
Although XL-CGD is the most common type of the disease worldwide, only 12 patients (12.9%) were XL-CGD in our study. The relatively high frequency of AR-CGD is probable due to widely common consanguineous marriages in Iran. 相似文献3.
Wolach B Broides A Zeeli T Gavrieli R de Boer M van Leeuwen K Levy J Roos D 《Journal of clinical immunology》2011,31(4):560-566
Background
Chronic granulomatous disease (CGD) is an immune deficiency syndrome caused by defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, the enzyme that generates reactive oxygen species (ROS) in phagocytizing leukocytes. This study evaluates the NADPH oxidase capacity in two X-linked CGD patients with mutations in gp91phox that alter the regions in this membrane-bound NADPH oxidase component involved in docking of the cytosolic component p47phox.Materials and Methods
Hydrogen peroxide and superoxide generation, bactericidal activity, and NADPH oxidase protein expression by the patients?? neutrophils were measured, and genetic analysis was performed.Results
We report two patients, each with a novel missense mutation in CYBB, the gene that encodes gp91phox. Surprisingly, neutrophils from these patients showed total absence of superoxide production, although they retained 13?C30% of the hydrogen peroxide production capability. We speculate that this is due to direct electron transfer from flavin adenine dinucleotide (FAD) in gp91phox to oxygen, leading to inefficient hydrogen peroxide formation instead of efficient superoxide production.Conclusions
X-linked CGD patients with mutations that alter the gp91phox protein in regions involved in docking of the cytosolic NADPH oxidase component p47phox may have higher than expected hydrogen peroxide generation capability. 相似文献4.
Khaoula Ben-Farhat Imen Ben-Mustapha Meriem Ben-Ali Karen Rouault Saber Hamami Najla Mekki Amel Ben-chehida Beya Larguèche Zohra Fitouri Selim Abdelmoula Monia khemiri Mohamed-Neji Guediche Samir Boukthir Sihem Barsaoui Jalel Chemli Mohamed-Ridha Barbouche 《Journal of clinical immunology》2016,36(6):547-554
Chronic granulomatous disease (CGD) is the prototypic functional neutrophil disorder caused by genetic defects in one of the five genes encoding the superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase subunits of phagocytes. Mutations causing the most prevalent form of CGD in western populations are located in the X-linked-CYBB gene. The four remaining autosomal recessive (AR) forms collectively account for one-third of CGD cases. We investigated the clinical and molecular features of eleven patients with CGD from 6 consanguineous families, originating from contiguous regions in the west of Tunisia. The patients’ clinical phenotype is characterized by a high incidence of mycobacterial infections. Five out of the eleven patients died despite treatment arguing in favor of a severe clinical form of CGD. These findings correlated with the absence of functional p67phox protein as well as the absence of residual reactive oxygen intermediates (ROI) production. Genetic analysis showed the presence, in all patients, of a unique mutation (c.257 + 2T > C) in NCF2 gene predicted to affect RNA splicing. Segregating analysis using nine polymorphic markers overlapping the NCF2 gene revealed a common haplotype spanning 4.1 Mb. The founder event responsible for this mutation was estimated to have arisen approximately 175 years ago. These findings will facilitate the implementation of preventive approaches through genetic counseling in affected consanguineous families. 相似文献
5.
Laila Ait Baba Fatima Ailal Naima El Hafidi Marjorie Hubeau Fabienne Jabot-Hanin Noufissa Benajiba Zahra Aadam Francesca Conti Caroline Deswarte Leila Jeddane Ayoub Aglaguel Ouafaa El Maataoui Ahmed Tissent Chafiq Mahraoui Jilali Najib Ruben Martinez-Barricarte Laurent Abel Norddine Habti Rachid Saile Jean-Laurent Casanova Jacinta Bustamante Hanane Salih Alj Ahmed Aziz Bousfiha 《Journal of clinical immunology》2014,34(4):452-458
6.
Manasi Kulkarni Mukesh Desai Maya Gupta Aparna Dalvi Prasad Taur Antony Terrance Sunil Bhat Mamta Manglani Revathi Raj Ira Shah Manisha Madkaikar 《Journal of clinical immunology》2016,36(8):774-784
Chronic granulomatous disease (CGD) is a group of inherited disorder of phagocytes, resulting from mutations in the components of the NADPH oxidase complex. Reduced or absent oxygen radical synthesis seen in these patients leads to impaired killing of intracellular bacteria and fungi. CGD clinically presents with recurrent and life-threatening infections as well as granulomatous inflammatory responses. p47phox encoded by the NCF1 gene is the most common autosomal recessive form of CGD which is often clinically milder. Here, we are presenting the data on clinical and immunological findings in 21 Indian patients with Del GT mutation in the NCF1 gene. Diagnosis of these patients was based on detailed clinical evaluation, measurement of respiratory burst activity by nitro blue tetrazolium and dihydrorhodamine-1,2,3 assay, expression of p47phox by flow cytometry, and molecular confirmation by GeneScan method. Seventeen male and four female patients with median age of onset of 1 year ranging from 1.5 months to 6 years were included in the study. Sixty-two percent (13 out of 21) of patients belonged to a consanguineous marriage with only one family having a history of a previous sibling death. Significant variability in clinical presentation was observed in spite of identical genetic defect ranging from asymptomatic to very severe presentation leading to early death or requiring transplantation. However, none of these patients showed difference in immunological parameters to account for this variability. Thus, this study highlights the phenotypic heterogeneity seen in these patients with Del GT mutation in the NCF1 gene and its implication in management of these patients. 相似文献
7.
Manasi Kulkarni Gouri Hule Martin de Boer Karin van Leeuwen Priyanka Kambli Jahnavi Aluri Maya Gupta Aparna Dalvi Snehal Mhatre Prasad Taur Mukesh Desai Manisha Madkaikar 《Journal of clinical immunology》2018,38(8):898-916
Background
Chronic granulomatous disease (CGD) is characterized by mutation in any one of the five genes coding NADPH oxidase components that leads to functional abnormality preventing the killing of phagocytosed microbes by affecting the progression of a respiratory burst. CGD patients have an increased susceptibility to infections by opportunistic and pathogenic organisms. Though initial diagnosis of CGD using a nitroblue tetrazolium (NBT) test or dihydrorhodamine (DHR) test is relatively easy, molecular diagnosis is challenging due to involvement of multiple genes, presence of pseudogenes, large deletions, and GC-rich regions, among other factors. The strategies for molecular diagnosis vary depending on the affected gene and the mutation pattern prevalent in the target population. There is a paucity of molecular data related to CGD for Indian population.Method
This report includes data for a large cohort of CGD patients (n?=?90) from India, describing the diagnostic approach, mutation spectrum, and novel mutations identified. We have used mosaicism in mothers and the expression pattern of different NADPH components by flow cytometry as a screening tool to identify the underlying affected gene. The techniques like Sanger sequencing, next-generation sequencing (NGS), and Genescan analysis were used for further molecular analysis.Result
Of the total molecularly characterized patients (n?=?90), 56% of the patients had a mutation in the NCF1 gene, 30% had mutation in the CYBB gene, and 7% each had mutation in the CYBA and NCF2 genes. Among the patients with NCF1 gene mutation, 82% of the patients had 2-bp deletion (DelGT) mutations in the NCF1 gene. In our cohort, 41 different mutations including 9 novel mutations in the CYBB gene and 2 novel mutations each in the NCF2, CYBA, and NCF1 genes were identified.Conclusion
Substantial number of the patients lack NCF1 gene on both the alleles. This is often missed by advanced molecular techniques like Sanger sequencing and NGS due to the presence of pseudogenes and requires a simple Genescan method for confirmation. Thus, the diagnostic approach may depend on the prevalence of affected genes in respective population. This study identifies potential gene targets with the help of flow cytometric analysis of NADPH oxidase components to design an algorithm for diagnosis of CGD in India. In Indian population, the Genescan method should be preferred as the primary molecular test to rule out NCF1 gene mutations prior to Sanger sequencing and NGS.8.
Baruch Wolach Ronit Gavrieli Martin de Boer Karin van Leeuwen Ofir Wolach Galia Grisaru-Soen Arnon Broides Amos Etzioni Raz Somech Dirk Roos 《Journal of clinical immunology》2018,38(2):193-203
Purpose
Chronic granulomatous disease (CGD) is an innate immune deficiency disorder of phagocytes, resulting from mutations in the components of the NADPH oxidase complex that impair the synthesis of oxygen radicals, thus rendering patients susceptible to recurrent infections and excessive hyperinflammatory responses. The most common autosomal recessive form of CGD is p47phox deficiency, which is often clinically milder than the more common X-linked recessive form. Here, we report data on genetics, clinical and biochemical findings in 17 CGD patients of Kavkazi origin with the nonsense mutation c.579G>A in the NCF1 gene, leading to p47phox deficiency.Methods
Diagnosis was based on detailed clinical evaluation, respiratory burst activity by cytochrome c reduction and dihydrorhodamine-1,2,3 (DHR) assay by flow cytometry, expression of p47phox by immunoblotting and molecular confirmation by DNA sequence analysis.Results
Twelve male and five female patients with median age at onset of 2.5 years (range 1 day to 9 years) were included in the study. The present cohort displays an encouraging 88% overall long-term survival, with median follow-up of 17 years. Clinical manifestations varied from mild to severe expression of the disease. Correlation between genotype and phenotype is unpredictable, although the Kavkazi patients were more severely affected than other patients with p47phox deficiency.Conclusions
Kavkazi CGD patients harbor a common genetic mutation that is associated with a heterogeneous clinical phenotype. Early diagnosis and proper clinical management in an experienced phagocytic leukocyte center is imperative to ensure favorable patient outcome. New treatment strategies are ongoing, but results are not yet conclusive.9.
M. A. Jakobsen T. L. Katzenstein N. H. Valerius D. Roos N. Fisker T. H. Mogensen P. Ø. Jensen T. Barington 《Scandinavian journal of immunology》2012,76(5):505-511
Chronic granulomatous disease (CGD) is a rare inherited disorder of the innate immune system caused by a defect in NADPH oxidase, leaving the granulocytes unable to kill invading microorganisms. CGD is caused by mutation in one of the five components gp91phox, p22phox, p47phox, p67phox and p40phox, encoded by the X‐linked CYBB gene and the autosomal CYBA, NCF1, NCF2 and NCF4 genes respectively. We have collected samples from all Danish patients with known CGD followed in the clinic or newly diagnosed during a 5‐year period, a cohort of 27 patients, and characterized them genetically. The cohort includes 10 male patients with X‐linked CGD and one female with extremely lyonized expression of a defective CYBB allele. Six patients had mutation in CYBA. Seven of 10 patients with a defect in NCF1 were homozygous for the common GT deletion, one was compound heterozygous for the GT deletion and a splice‐site mutation, and two patients were homozygous for a nonsense mutation in exon 7. Three novel mutations were detected, a deletion of exon 6 in CYBA, a duplication of exon 8–13 in CYBB and a splice site mutation in intron 7 of NCF1. 相似文献
10.
Roos D de Boer M Köker MY Dekker J Singh-Gupta V Ahlin A Palmblad J Sanal O Kurenko-Deptuch M Jolles S Wolach B 《Human mutation》2006,27(12):1218-1229
Chronic granulomatous disease (CGD) is an inherited immunodeficiency caused by defects in any of four genes encoding components of the leukocyte nicotinamide dinucleotide phosphate, reduced (NADPH) oxidase. One of these is the autosomal neutrophil cytosolic factor 1 (NCF1) gene encoding the p47phox protein. Most (>97%) CGD patients without p47phox (A47 degrees CGD) are homozygotes for one particular mutation in NCF1, a GT deletion in exon 2. This is due to recombination events between NCF1 and its two pseudogenes (psiNCF1) that contain this GT deletion. We have previously set up a gene-scan method to establish the ratio of NCF1 genes and pseudogenes. With this method we now found, in three CGD families patients with the normal number of two intact NCF1 genes (and four psiNCF1 genes) and in six CGD families, patients with one intact NCF1 gene (and five psiNCF1 genes). All patients lacked p47phox protein expression. These results indicate that other mutations were present in their NCF1 gene than the GT deletion. To identify these mutations, we designed PCR primers to specifically amplify the cDNA or parts of the genomic DNA from NCF1 but not from the psiNCF1 genes. We found point mutations in NCF1 in eight families. In another family, we found a 2,860-bp deletion starting in intron 2 and ending in intron 5. In six families the patients were compound heterozygotes for the GT deletion and one of these other mutations; in two families the patients had a homozygous missense mutation; and in one family the patient was a compound heterozygote for a splice defect and a nonsense mutation. Family members with either the GT deletion or one of these other mutations were identified as carriers. This knowledge was used in one of the families for prenatal diagnosis. 相似文献
11.
Pandiarajan Vignesh Amit Rawat Ankur Kumar Deepti Suri Anju Gupta Yu L Lau Koon W Chan Surjit Singh 《Journal of clinical immunology》2017,37(2):109-112
Chronic granulomatous disease (CGD) is an inheritable and genetically heterogeneous disease resulting from mutations in different subcomponents of the NADPH oxidase system. Mutations in the NCF2 gene account for <5% of all cases of CGD. We analyzed the clinical and laboratory findings of CGD with mutations in the NCF2 gene from amongst our cohort of CGD patients. A homozygous mutation (c.835_836delAC, p.T279fsX294), a deletion in NCF2 gene was found in two cases. In the third case, two heterozygous mutations were detected, IVS13-2A>T on one allele and c.1099C>T (p.) on the other allele. The mother of this child was a carrier for the IVS13-2A>T mutation. All three cases had colitis, and it was the initial symptom in two patients. One of the patients also developed a lung abscess due to Nocardia cyriacigeorgica. 相似文献
12.
I. Elnour S. AlKindi C. Lapoumeroulie S. Al‐Maamari A. Pathare D. Dennison R. Krishnamoorthy 《Clinical genetics》2015,87(2):185-189
Chronic granulomatous disease (CGD), a rare inherited disorder of the innate immune system, results from mutations in any one of the five genes encoding the subunits of the nicotinamide adenine dinucleotide phosphate‐oxidase (NADPH) oxidase enzyme, and is characterized by recurrent life‐threatening bacterial and fungal infections. Molecular analysis of 14 Omani CGD patients from 10 families, diagnosed to have CGD on clinical (recurrent infections) and biochemical grounds (positive for both the nitroblue tetrazolium (NBT) test and the dihydrorhodamine (DHR‐1,2,3 assay), revealed that only one patient had X‐linked CGD, with a large deletion involving both the gp91‐phox gene (CYBB) and the McLeod gene (XK). The remaining 13 patients were all homozygotes from a previously described c.579G>A (p.Trp193X) mutation in the NCF1 gene on chromosome 7, responsible for autosomal recessive CGD (AR‐CGD). Although X‐linked CGD is the most common type of CGD disorder in most population groups, AR‐CGD is the most prevalent type in Oman. 相似文献
13.
Shaghayegh Tajik Mohsen Badalzadeh Mohammad Reza Fazlollahi Massoud Houshmand Nasrin Bazargan Masoud Movahedi Maryam Mahlouji Rad Seyed Alireza Mahdaviani Setareh Mamishi Ghamar Taj Khotaei Davood Mansouri Fariborz Zandieh Zahra Pourpak 《Scandinavian journal of immunology》2019,90(1)
One of the components of NADPH oxidase is p47‐phox, encoded by NCF1 gene. This study aims to find new genetic changes and clinical features in 38 Iranian patients with autosomal recessive chronic granulomatous disease (AR‐CGD) caused by NCF1 gene defect. Patients who had abnormal NBT and DHR‐1,2,3 assay with loss of p47‐phox in Western blotting were included in this study. After recording demographic and clinical data, PCR amplification was performed followed by direct sequencing for all exons and exon‐intron boundaries. The most common form of CGD in Iran was AR‐CGD due to consanguinity marriages. Among patients with AR‐CGD, NCF1 deficiency was found to be more common than other forms. Cutaneous involvements (53%), pulmonary infections (50%) and lymphadenopathy (29%) were more prevalent than other clinical manifestations of CGD. Mutation analysis of NCF1 gene identified five different mutations. Homozygous delta GT deletion (c.75_76delGT) was the most frequent mutation and was detected in more than 63% of families. Six families had a nonsense mutation in exon 7 (c.579G > A). Two novel mutations were found in exon 4 in two families, including a missense mutation (c.328C > T) and a nine‐nucleotide deletion (c.331_339delTGTCCCCAC). Genetic detection of these mutations may result in early diagnosis and prevention of possible complications of the disease. This could be useful for timely decision‐making for haematopoietic stem cell transplantation and for carrier detection as well as prenatal diagnosis of next children in the affected families. Our findings might help to predict outcomes, raise awareness and help effective treatment in these patients. 相似文献
14.
Robina Khan Niazi Mette Hollensted Christian Theil Have Niels Grarup Oluf Pedersen Asmat Ullah Gulbin Shahid Wasim Ahmad Asma Gul Torben Hansen 《BMC medical genetics》2018,19(1):199
Background
Mutations in the genes encoding leptin (LEP), the leptin receptor (LEPR), and the melanocortin 4 receptor (MC4R) are known to cause severe early-onset childhood obesity. The aim of the current study was to examine the prevalence of damaging LEP, LEPR, and MC4R mutations in Pakistani families having a recessive heritance of early-onset obesity.Methods
Using targeted resequencing, the presence of rare mutations in LEP, LEPR, and MC4R, was investigated in individuals from 25 families suspected of having autosomal recessive early-onset obesity. Segregation patterns of variants were assessed based on chip-based genotyping.Results
Homozygous LEPR variants were identified in two probands. One carried a deletion (c.3260AG) resulting in the frameshift mutation p.Ser1090Trpfs*6, and the second carried a substitution (c.2675C?>?G) resulting in the missense mutation p.Pro892Arg. Both mutations were located within regions of homozygosity shared only among affected individuals. Both probands displayed early-onset obesity, hyperphagia and diabetes. No mutations were found in LEP and MC4R.Conclusions
The current study highlights the implication of LEPR mutations in cases of severe early-onset obesity in consanguineous Pakistani families. Through targeted resequencing, we identified novel damaging mutations, and our approach may therefore be utilized in clinical testing or diagnosis of known forms of monogenic obesity with the aim of optimizing obesity treatment.15.
Marcus Gentsch Aneta Kaczmarczyk Karin van Leeuwen Martin de Boer Magdalena Kaus‐Drobek Marie‐Claire Dagher Petra Kaiser Peter D. Arkwright Manfred Gahr Angela Rösen‐Wolff Matthias Bochtler Elizabeth Secord Pamela Britto‐Williams Gulam Mustafa Saifi Anne Maddalena Ghassan Dbaibo Jacinta Bustamante Jean‐Laurent Casanova Dirk Roos Joachim Roesler 《Human mutation》2010,31(2):151-158
Mutations that impair expression or function of the components of the phagocyte NADPH oxidase complex cause chronic granulomatous disease (CGD), which is associated with life‐threatening infections and dysregulated granulomatous inflammation. In five CGD patients from four consanguineous families of two different ethnic backgrounds, we found similar genomic homozygous deletions of 1,380 bp comprising exon 5 of NCF2, which could be traced to Alu‐mediated recombination events. cDNA sequencing showed in‐frame deletions of phase zero exon 5, which encodes one of the tandem repeat motifs in the tetratricopeptide (TPR4) domain of p67‐phox. The resulting shortened protein (p67Δ5) had a 10‐fold reduced intracellular half‐life and was unable to form a functional NADPH oxidase complex. No dominant negative inhibition of oxidase activity by p67Δ5 was observed. We conclude that Alu‐induced deletion of the TPR4 domain of p67‐phox leads to loss of function and accelerated degradation of the protein, and thus represents a new mechanism causing p67‐phox–deficient CGD. Hum Mutat 30:1–8, 2009. © 2009 Wiley‐Liss, Inc. 相似文献
16.
Huan Xu Wen Tian Shu-Juan Li Lu-Ying Zhang Wei Liu Yao Zhao Zhi-Yong Zhang Xue-Mei Tang Mo Wang Dao-Qi Wu Ji-Sheng Shi Yuan Ding Xiao-Dong Zhao Xi-Qiang Yang Li-Ping Jiang 《Journal of clinical immunology》2014,34(6):633-641
Purpose
Chronic granulomatous disease (CGD) is an inherited disorder, with phagocytes failing to produce antimicrobial superoxide due to deficient NADPH oxidase activity. Mutations in the gene encoding CYBB are responsible for the majority of the CGD cases. To date, there have been no reports on large samples of children with CGD in China. Therefore, in this study, we described the clinical and molecular features of 38 suspected CGD patients from 36 unrelated Chinese families.Methods
Clinical diagnosis was performed using dihydrorhodamine assays detected by flow cytometry. Molecular analysis was used to identify underlying CGD-causative genes.Results
The mean age of onset in our 38 patients was 3.4 months, while the mean age at diagnosis was 31.7 months. Apart from recurrent pneumonia and abscesses, tuberculosis (TB) and Bacille Calmette-Guerin (BCG) infections were notable features in our cohort. Overall, 17 cases died and patient 1 did not participate in the follow-up period . In total, we identified 29 different CYBB gene mutations in 31 patients. We found NCF1 and CYBA mutations in 3 and 2 patients, respectively. In addition, we identified 31 carriers and prenatally diagnosed 4 CGD and 4 healthy fetuses.Conclusions
The results of our study demonstrate that children with BCG infections or recurrent TB infections should have immune function screening tests performed. Moreover, newborns with family histories of primary immunodeficiency diseases should avoid of BCG vaccination. Molecular analysis is an important tool for identifying patients, carriers, and high-risk CGD fetuses. 相似文献17.
Rabab El Hawary Safa Meshaal Caroline Deswarte Nermeen Galal Mahitab Abdelkawy Radwa Alkady Dalia Abd Elaziz Tomas Freiberger Barbora Ravcukova Jiri Litzman Jacinta Bustamante Taghrid Gaafar Aisha Elmarsafy 《Journal of clinical immunology》2016,36(6):610-618
Introduction
Chronic granulomatous disease (CGD) is an inherited mutational defect in any of the NADPH oxidase complex, CYBB (gp91-phox), NCF1 (p47-phox), CYBA (p22-phox), NCF2 (p67-phox), or NCF4 (p40-phox) leading to inability of phagocytes to perform effective respiratory burst and thus diminished killing of bacteria and fungi. The identification of defective proteins aids in establishing a diagnosis prior to genetic analysis, which is rather labor-intensive, expensive, and time-consuming.Aim
The present study aims at assessing the NADPH proteins by performing the intracellular staining with specific monoclonal antibodies and their assessment on flow cytometry. The use of flow cytometry is less laborious and faster to perform than western blot. It also confirms the diagnosis of CGD and detects the affected components allowing proper management of patients.Materials and Methods
Twenty-eight patients from 25 different kindred, clinically suspected as CGD were recruited in Egypt. Dihydrorhodamine test was performed to confirm the diagnosis of the patients. Intracellular staining of NADPH components using specific monoclonal antibodies was performed followed by flow cytometric analysis.Results
The present study revealed that the most common defective protein in our cohort is p22-phox, found in 13 patients (46.4 % of cases) followed by p47-phox in 8 patients (28.6 %), gp91-phox in 5 patients (17.9 %), and finally p67-phox in 2 patients (7.1 %).Conclusion
In countries with limited resources and yet large number of CGD patients, the analysis of the defective proteins by flow cytometry is an optimum solution for confirming the diagnosis and is a step for targeted sequencing in families seeking prenatal diagnosis.18.
Qinhua?Zhou Xiaoying?Hui Wenjing?Ying Jia?Hou Wenjie?Wang Danru?Liu Ying?Wang Yeheng?Yu Jingyi?Wang Jinqiao?Sun Qian?Zhang Xiaochuan?Wang
Purpose
Clinical diagnosis and treatment for chronic granulomatous disease (CGD) have advanced greatly in recent years. However, CGD patients in China have unique clinical features and infection spectrums, which are challenging to their caretakers. Here, we summarized the clinical characteristics, genetic features, treatment, and prognosis of CGD in a single center in Shanghai.Methods
One hundred sixty-nine CGD patients were recruited between January 2004 and May 2017 based on clinical diagnosis. Electronic medical charts were reviewed to collect clinical data.Results
Among the 169 patients recruited, CYBB mutations were identified in 150 cases, whereas CYBA mutations were identified in 7 cases, NCF1 in 5, and NCF2 in 7. The medium age at onset was 1 month (interquartile range 1–3). The medium age at diagnosis was 8 months (interquartile range 3–19). The most common infection sites were the lung (95.9%), lymph node (58.5%), skin (45.4%), intestinal (43.1%), and perianal (38.5%). Bacillus Calmette-Guérin (BCG) infections were common (59.2%). In addition, other non-infectious complications were also common, including anemia (55.4%) and impaired liver functions (34.6%). Thirty-one patients received stem cell transplantation. By the end of this study, 83/131 patients survived.Conclusions
Similar to other non-consanguineous populations, X-linked CGD accounted for the majority of the cases in China. However, BCG infections were a clinical challenge unique to China. In addition, severe infections were the major cause of death and the overall mortality was still high in China.19.
Guruswamy Neethirajan Subbaiah Ramasamy Krishnadas Perumalsamy Vijayalakshmi Shetty Shashikant Periasamy Sundaresan 《BMC medical genetics》2004,5(1):1-7
Background
Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disease with a high risk for colorectal and endometrial cancer caused by germline mutations in DNA mismatch-repair genes (MMR). HNPCC accounts for approximately 2 to 5% of all colorectal cancers. Here we present 6 novel mutations in the DNA mismatch-repair genes MLH1, MSH2 and MSH6.Methods
Patients with clinical diagnosis of HNPCC were counselled. Tumor specimen were analysed for microsatellite instability and immunohistochemistry for MLH1, MSH2 and MSH6 protein was performed. If one of these proteins was not detectable in the tumor mutation analysis of the corresponding gene was carried out.Results
We identified 6 frameshift mutations (2 in MLH1, 3 in MSH2, 1 in MSH6) resulting in a premature stop: two mutations in MLH1 (c.2198_2199insAACA [p.N733fsX745], c.2076_2077delTG [p.G693fsX702]), three mutations in MSH2 (c.810_811delGT [p.C271fsX282], c.763_766delAGTGinsTT [p.F255fsX282], c.873_876delGACT [p.L292fsX298]) and one mutation in MSH6 (c.1421_1422dupTG [p.C475fsX480]). All six tumors tested for microsatellite instability showed high levels of microsatellite instability (MSI-H).Conclusions
HNPCC in families with MSH6 germline mutations may show an age of onset that is comparable to this of patients with MLH1 and MSH2 mutations. 相似文献20.
Rand Arnaout Sahar Al Shorbaghi Hasan Al Dhekri Hamoud Al-Mousa Abdulaziz Al Ghonaium Bandar Al Saud Saleh Al Muhsen Lina Al Baik Abbas Hawwari 《Journal of clinical immunology》2013,33(4):871-875