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1.
X-linked agammaglobulinemia (XLA) is an immunodeficiency caused by mutations in the Bruton tyrosine kinase (BTK) gene. Twenty Australian patients with an XLA phenotype, from 15 unrelated families, were found to have 14 mutations. Five of the mutations were previously described c.83G>A (p.R28H), c.862C>T (p.R288W), c.904G>A (p.R302G), c.1535T>C (p.L512P), c.700C>T (p.Q234X), while nine novel mutations were identified: four missense c.82C>A (p.R28S), c.494G>A (p.C165Y), c.464G>A (p.C155Y), c.1750G>A (p.G584E), one deletion c.142_144delAGAAGA (p.R48_G50del), and four splice site mutations c.241-2A>G, c.839+4A>G, c.1350-2A>G, c.1566+1G>A. Carrier analysis was performed in 10 mothers and 11 female relatives. The results of this study further support the notion that molecular genetic testing represents an important tool for definitive and early diagnosis of XLA and may allow accurate carrier status and prenatal diagnosis. 相似文献
2.
Tani SM Wang Y Kanegane H Futatani T Pinto J Vilela MM Miyawaki T 《Human mutation》2002,20(3):235-236
Mutations in the Bruton tyrosine kinase (BTK) gene are responsible for X-linked agammaglobulinemia (XLA), which is characterized by recurrent bacterial infections, profound hypogammaglobulinemia, and decreased numbers of mature B cells in the peripheral blood. We evaluated 17 male Brazilian patients from 13 unrelated families who showed markedly reduced numbers of blood B cells and hypogammaglobulinemia. BTK gene analysis detected mutations in 10 of the 13 presumed XLA families. Seven mutations (Q196X, G613D, R28L, 251-273del, Q234X, H364P, and R13X) had been reported previously, whereas the remaining three mutations (M501T, IVS15+1G>C, and IVS14+1G>A) were novel. Mutation IVS15+1G>C occurred in a splice donor site and caused exons 15 and 16 to be skipped, and IVS14+1G>A might cause exon 14 to be skipped. Flow cytometry revealed deficient expression of BTK protein in 10 of the 13 families. This is the first report of the diagnosis of XLA by analysis of mutations of the BTK gene in Brazilian patients. 相似文献
3.
4.
Sedivá A Smith CI Asplund AC Hadac J Janda A Zeman J Hansíková H Dvoráková L Mrázová L Velbri S Koehler C Roesch K Sullivan KE Futatani T Ochs HD 《Journal of clinical immunology》2007,27(6):640-646
X-linked agammaglobulinemia (XLA) is characterized by low levels of B-lymphocytes with early-onset, recurrent, microbial infections
occasionally causing neurological symptoms. We observed an atypical clinical course of XLA, complicated since early childhood
with neurological impairment, progressive sensorineural deafness, and dystonia in six boys of four unrelated families. The
neurologic symptoms suggested the diagnosis of Mohr–Tranebjaerg syndrome, caused by mutations in the TIMM8A gene, previously known as DDP1, and located centromerically of BTK. Deafness dystonia peptide (DDP1) participates in neurological development and is a part of the mitochondrial protein import
pathway. Mutation analysis of the BTK gene revealed gross deletions of different lengths in all patients, in one case extending approximately 196 kb, including
the genes TIMM8A, TAF7L, and DRP2. The most prominent clinical findings of this contiguous deletion syndrome are the combination of immunodeficiency and sensorineural
deafness, which were present in all affected boys. The severity of symptoms, however, did not correlate with the extent of
the deletion. 相似文献
5.
Okoh MP Kainulainen L Heiskanen K Isa MN Varming K Ruuskanen O Vihinen M 《Human mutation》2002,20(6):480-481
Mutations in the gene encoding Bruton tyrosine kinase (BTK) result in X-linked agammaglobulinemia (XLA), an immunodeficiency of antibody defect. By using base excision sequence scanning method (BESS) followed by direct sequencing we found in seven unrelated families with a classical XLA phenotype various mutations including six novel mutations (g.64512_64513insC, c.108_109insG, c.1700_1701insACTACAG, g.51375_51376GC>TG, g.63991_63992insGGTAGAAAAAA, c.1956_1957insCA) and a previously known silent polymorphism (c.2031C>T). Except for two mutations, the alterations affect the kinase domain. There was exceptionally high proportion of insertions in the cohort. Frameshift insertion was found altogether in five patients, three of which are on introns, one in upstream region, and one in exon 18 leading to frameshift mutation and truncation of the protein. In the intron 4 there is a substitution of two bases. Carrier detection was performed in four families. In one case the mutation was found to be de novo. 相似文献
6.
Volker Schuster Silvia Seidenspinner Hans Wolfgang Kreth 《American journal of medical genetics. Part A》1996,63(1):318-322
X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency disease with a block in differentiation from pre-B to B cells resulting in a selective defect in the humoral immune response. Affected males have very low concentrations of serum immunoglobulins leading predominantly to recurrent bacterial infections beginning at age 6 to 18 months. The gene responsible for XLA was identified recently to encode a cytoplasmatic tyrosine kinase (Bruton's tyrosine kinase, BTK). We have analyzed the BTK gene in a large family in which two brothers presented with the severe phenotype of XLA. Genomic DNA of affected boys and from healthy relatives was amplified by PCR with primers specific for the putative promoter region and for all 19 exons, including flanking intron boundaries, and subsequently screened for mutations using single strand conformation polymorphism (SSCP) analysis. Altered single strand band patterns were found using primers specific for exon 10, 15, and 18. Direct cycle-sequencing of these BTK segments detected two known polymorphisms in intron 14 and in exon 18. Sequencing of exon 10 from two boys with XLA demonstrated a novel point mutation in the SH2 domain of BTK. Direct identification of healthy female carriers in three generations was performed by amplification mutagenesis using PCR with a modified first primer. This method can easily be applied also to prenatal diagnosis. © 1996 Wiley-Liss, Inc. 相似文献
7.
目的通过中国X连锁无丙种球蛋白血症(XLA)患儿临床表现、免疫功能评价、Bruton's酪氨酸激酶(BTK)的表达及BTK基因突变分析,分析基因型和表型间可能存在的关系。方法选取拟诊为XLA患儿,使用抗BTK单克隆抗体通过流式细胞技术分析单核细胞BTK蛋白表达。采用RT-PCR获得患儿cDNA,使用8对不同引物分2步扩增BTKcDNA,PCR产物测序。突变结果通过对DNA外显子相应部位扩增、测序证实。并对确诊XLA患儿的母亲及家族中部分亲属进行BTK蛋白表达和BTK基因分析。结果①40/50例原发性低丙种球蛋白血症患儿经BTK基因突变分析确诊为XLA,以错义突变(16例,40.0%)和无义突变(13例,32.5%)为主。②突变类型为错义突变的患儿平均起病年龄为(1.4±1.1)岁,其他突变类型患儿为(1.4±0.7)岁,差异无统计学意义(P=0.45)。错义突变的发生率随年龄的增长呈上升趋势,无义突变的发生率呈下降趋势。③34/40例(85.0%)B细胞〈0.1%;4例(10.0%)B细胞在1%~2%,其中错义突变2例,无义突变1例,剪接突变1例;2例(5.0%)B细胞为2%,均为错义突变。④血清IgG〈3g·L-1患儿BTK基因突变类型以错义突变和无义突变为主。⑤错义突变患儿BTK蛋白表达水平与其他突变类型无显著差异。⑥6/21例(28.6%)2031C/T多态性患儿伴有严重的关节炎,3/19例(15.8%)无多态性患儿有关节炎表现。⑦28/32例(87.5%)XLA患儿母亲为BTK基因杂合型。结论错义突变可能与确诊年龄较大有关,且某些位点的错义突变可能与较高的外周血B细胞数量和血清IgG水平及正常的BTK蛋白表达水平有关。BTK基因多态性(2031C/T)可能增加关节炎的风险。 相似文献
8.
Bruton's tyrosine kinase (Btk) has been identified as the protein responsible for the primary immunodeficiency X-linked agammaglobulinemia (XLA) and has been described as a new member of Srcrelated cytoplasmic protein tyrosine kinases. We have recently characterized the structure of the entire gene encoding Btk and developed a polymerase chain reaction (PCR)-based assay to detect germline mutations within it. In this report we describe six mutations, five of which are novel, of the Btk gene in patients with XLA and demonstrate the inheritance pattern of the defect within the families of the affected individuals. The mutations found include two nonsense and two missense mutations, a single base deletion at an intron acceptor splice site, and a 16-bp insertion. A single Strand conformation polymorphism was also found in the 5′ end of intron 8 with the same assay. This technique has provided a powerful tool for direct analysis of the Btk gene for the diagnosis of XLA and carrier detection. The identification of new mutations may eventually reveal the role of Btk in the signaling pathways involved in B-cell development. © 1995 Wiley-Liss, Inc. 相似文献
9.
Characterization of All Possible Single‐Nucleotide Change Caused Amino Acid Substitutions in the Kinase Domain of Bruton Tyrosine Kinase
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Jouni Väliaho Imrul Faisal Csaba Ortutay C. I. Edvard Smith Mauno Vihinen 《Human mutation》2015,36(6):638-647
Knowledge about features distinguishing deleterious and neutral variations is crucial for interpretation of novel variants. Bruton tyrosine kinase (BTK) contains the highest number of unique disease‐causing variations among the human protein kinases, still it is just 10% of all the possible single‐nucleotide substitution‐caused amino acid variations (SNAVs). In the BTK kinase domain (BTK‐KD) can appear altogether 1,495 SNAVs. We investigated them all with bioinformatic and protein structure analysis methods. Most disease‐causing variations affect conserved and buried residues disturbing protein stability. Minority of exposed residues is conserved, but strongly tied to pathogenicity. Sixty‐seven percent of variations are predicted to be harmful. In 39% of the residues, all the variants are likely harmful, whereas in 10% of sites, all the substitutions are tolerated. Results indicate the importance of the entire kinase domain, involvement in numerous interactions, and intricate functional regulation by conformational change. These results can be extended to other protein kinases and organisms. 相似文献
10.
Basile N Danielian S Oleastro M Rosenzweig S Prieto E Rossi J Roy A Zelazko M 《Journal of clinical immunology》2009,29(1):123-129
Introduction Argentina has a large number of patients with definite diagnosis of X-linked agammaglobulinemia reported in the Latin-American
registry. Forty-nine of them were seen in our referral pediatric hospital, between 1987 and 2005.
Results and Discussion A retrospective study of clinical, laboratory, and molecular data showed that respiratory tract infections were the most frequent
initial clinical presentation and the most common among all manifestations prior to diagnosis (69%). Up to diagnosis, we found
a high frequency of severe infections (sepsis, 14% and meningitis, 16%) and a high proportion of patients with chronic lung
disease. During follow-up, the development of chronic lung disease was significantly related with age at diagnosis and inappropriate
treatment.
Conclusion Although molecular diagnosis has been available in our center for the past 10 years, there is no doubt that awareness for
early recognition of immunodeficiency should be improved through broader and more comprehensive education programs emphasizing
characteristics of patients with immunodeficiencies.
Natalia Basile and Silvia Danielian contributed equally to this work 相似文献
11.
Jo EK Wang Y Kanegane H Futatani T Song CH Park JK Kim JS Kim DS Ahn KM Lee SI Park HJ Hahn YS Lee JH Miyawaki T 《Journal of human genetics》2003,48(6):322-326
Mutations in the Bruton's tyrosine kinase (BTK) gene are responsible for X-linked agammaglobulinemia (XLA). We identified BTK mutations in six patients with presumed XLA from unrelated Korean families. Four out of six mutations were novel: two missense
mutations (P565T, C154Y), a point mutation in a splicing donor site (IVS11+1G>A), and a large deletion (a 6.1-kb deletion
including BTK exons 11–18). The large deletion, identified by long-distance PCR, revealed Alu-Alu mediated recombination extended from an Alu sequence in intron 10 to another Alu sequence in intron 18, spanning a distance of 6.1 kb. The two known mutations consisted of one missense (G462D) mutation,
and a point mutation in a splicing acceptor site (IVS7−9A>G). This study suggests that large genomic rearrangements involving Alu repeats are few but an important component of the spectrum of BTK mutations. 相似文献
12.
Summary Within a short time interval the specific gene defects causing three X-linked human immunodeficiencies, agammaglobulinemia (XLA), hyper-IgM syndrome (HIGM), and severe combined immunodeficiency (XSCID), have been identified. These represent the first human disease phenotypes associated with each of three gene families already recognized to be important in lymphocyte development and signaling: XLA is caused by mutations of a B cell-specific intracellular tyrosine kinase; HIGM, by mutations in the TNF-related CD40 ligand, through which T cells deliver helper signals by direct contact with B cell CD40; and XSCID, by mutations in the chain of the lymphocyte receptor for IL-2. Each patient mutation analyzed to date has been unique, representing both a challenge for genetic diagnosis and management and an important resource for dissecting molecular domains and understanding the physiologic function of the gene products.Formerly at Department of Pediatrics, University of Pennsylvania School of Medicine and Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 相似文献
13.
N. Jan Chalupny Alejandro Aruffo James M. Esselstyn Po-Ying Chan Jürgen Bajorath James Blake Lisa K. Gilliland Jeffrey A. Ledbetter Mark A. Tepper 《European journal of immunology》1995,25(10):2978-2984
CD 19 is a B cell surface protein capable of forming non-covalent molecular complexes with a number of other B cell surface proteins including the CD21/CD81/Leu-13 complex as well as with surface immunoglobulin. CD19 tyrosine phosphorylation increases after B cell activation, and is proposed to play a role in signal transduction through its cytoplasmic domain, which contains nine tyrosine residues. Several second messenger proteins have been shown to immunoprecipitate with CD 19, including p59 Fyn (Fyn), p59 Lyn (Lyn) and phosphatidylinositol-3 kinase (PI-3 kinase). These associations are predicted to occur via the src-homology 2 (SH2) domains of the second messenger proteins. Two of the cytoplasmic tyrosines in the CD 19 cytoplasmic region contain the consensus binding sequence for the PI-3 kinase SH2 domain (YPO4-X-X-M). However, the reported consensus binding sequence for the Fyn and Lyn SH2 domains (YPO4-X-X-I/L) is not found in CD 19. We investigated the capacity of CD 19 cytoplasmic tyrosines to bind both Fyn and PI-3 kinase SH2-domain fusion proteins. In activated B cells, both Fyn and PI-3 kinase SH2-domain fusion proteins precipitate CD 19. Using synthetic tyrosine-phosphorylated peptides comprising each of the CD 19 cytoplasmic tyrosines and surrounding amino acids, we investigated the ability of the Fyn SH2 and PI-3 kinase SH2 fusion proteins to bind to the different CD 19 cytoplasmic phosphotyrosine peptides. ELISA revealed that the two CD 19 cytoplasmic tyrosine residues contained within the Y-X-X-M sequences (Y484 and Y515) bound preferentially to the PI-3 kinase SH2-domain fusion proteins. Two different tyrosines (Y405 and Y445) bound preferentially to the Fyn SH2-domain fusion protein via a novel sequence, Y-E-N-D/E, different from that previously reported for the Fyn SH2 domain. In precipitation studies, peptide Y484 was able to compete with tyrosine phosphorylated CD 19 specifically for binding to the PI-3 kinase SH2 domain fusion proteins, while peptides Y405 and Y445 were able to compete specifically for binding to the Fyn SH2 domain fusion proteins. These results indicate that CD19 may be capable of binding both Fyn and PI-3 kinase concurrently, suggesting a mechanism for CD 19 signal transduction, in which binding of PI-3 kinase to the Fyn SH3 domain results in activation of PI-3 kinase. 相似文献
14.
Roland Spiegel Albert R. La Spada Wolfram Kress Kenneth H. Fischbeck Werner Schmid 《Human mutation》1996,8(1):32-37
Expansion of trinucleotide repeats has now been associated with eight inherited diseases: X-linked spinal and bulbar muscular atrophy, two fragile X syndromes, myotonic dystrophy, Huntington's disease, spinocerebellar ataxia type I, dentatorubral pallidoluysian atrophy and Machado-Joseph disease. It has been shown that these expanded DNA repeats are unstable in number when transmitted from parents to offspring (“meiotic instability”), while somatic variation in repeat number has also been found in the fragile X syndrome and myotonic dystrophy. Moderate meiotic instability has been demonstrated in X-linked spinal and bulbar muscular atrophy (SBMA, Kennedy's disease). In order to determine if the expanded CAG repeat in SBMA also shows somatic instability, we compared different tissues from two patients with SBMA. We then examined the in vitro stability of the CAG repeat expansion by analyzing fibroblast cell cultures. Length comparison of expanded CAG repeats from all these materials clearly demonstrates that the CAG trinucleotide repeat in SBMA does not exhibit somatic variation. © 1996 Wiley-Liss, Inc. 相似文献
15.
Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled immune activation and is traditionally associated with inherited gene defects or acquired causes. In addition to abnormalities in cytotoxic granules and lysosomes, various primary immune deficiency disorders (PID) have been identified among patients suffering from HLH. Our purpose was twofold: to better characterize and detail the association between PID and HLH. 相似文献
16.
V. Schuster Teodor Podskarbi Holger Ottensmeier Markus Haubner Yoon Sook Shin 《Journal of molecular medicine (Berlin, Germany)》1998,76(10):715-719
Classical galactosemia, characterized clinically by acute hepatic dysfunction, sepsis, cataract, and failure to thrive, is
caused by deficiency of galactose-1-phosphate uridyltransferase (GALT). Galactose restriction normalizes these acute symptoms;
however, long-term complications such as intellectual deficits and ovarian failure are conspicuous in the majority of patients.
Here we report two Turkish siblings with classical galactosemia. The clinical course of the two children differed markedly:
only the older girl suffered from severe acute symptoms during the neonatal period, and she developed greater mental retardation
than her younger affected brother. The functional activity of GALT was virtually absent in each affected children. The mother
and two healthy siblings exhibited approximately 50% normal GALT activity and the father approximately 25%. Molecular analysis
revealed that these two galactosemic siblings were homozygous for a stop codon mutation of E340X in GALT exon 10. Moreover,
two additional mutations, a neutral polymorphism L218L and N314D, which are typical for the Duarte-1 variant, were found in
the same GALT allele. The two healthy siblings and the parents were heterozygous for these combinations of mutations. In addition,
the father’s second GALT allele revealed three intron mutations at nucleotide position 1105 (G→C), 1323 (G→A) and 1391 (G→A)
and the N314D mutation, which correspond to the mutations of Duarte-2 variant. Our findings indicate that in classical galactosemia
several distinct mutations can be present in one allele (in cis) of the GALT gene. Therefore it seems to be necessary to examine all introns and exons of the GALT gene in galactosemic patients
who do not carry the Q188R mutation or another frequent mutation in the GALT gene.
Received: 28 January 1998 / Accepted: 20 May 1998 相似文献
17.
Pedro M. Rodríguez Cruz Judith Cossins Jonathan Cheung Susan Maxwell Sandeep Jayawant Ruth Herbst Dominic Waithe Alexandr P. Kornev Jacqueline Palace David Beeson 《Human mutation》2020,41(3):619-631
MUSK encodes the muscle‐specific receptor tyrosine kinase (MuSK), a key component of the agrin‐LRP4‐MuSK‐DOK7 signaling pathway, which is essential for the formation and maintenance of highly specialized synapses between motor neurons and muscle fibers. We report a patient with severe early‐onset congenital myasthenic syndrome and two novel missense mutations in MUSK (p.C317R and p.A617V). Functional studies show that MUSK p.C317R, located at the frizzled‐like cysteine‐rich domain of MuSK, disrupts an integral part of MuSK architecture resulting in ablated MuSK phosphorylation and acetylcholine receptor (AChR) cluster formation. MUSK p.A617V, located at the kinase domain of MuSK, enhances MuSK phosphorylation resulting in anomalous AChR cluster formation. The identification and evidence for pathogenicity of MUSK mutations supported the initiation of treatment with β2‐adrenergic agonists with a dramatic improvement of muscle strength in the patient. This work suggests uncharacterized mechanisms in which control of the precise level of MuSK phosphorylation is crucial in governing synaptic structure. 相似文献
18.
Somatic mutations of PIK3CA are found in 20% to 40% of invasive breast cancers. To investigate the frequency of PIK3CA mutations in the intraductal proliferative lesions of the breast, which are precursor lesions for invasive carcinoma, we analyzed 125 intraductal proliferative lesions and 108 invasive breast cancer tissues for PIK3CA mutations in this study. Target cells were precisely isolated using a laser capture microdissection (LCM) system. Genomic DNA was extracted with QIAmp DNA Micro Kit. PCR amplification was done for exons 9 and 20 of PIK3CA, where 90% of mutations clustered, and the products were directly sequenced. Forty-six missense mutations were identified in total, of which, 14 and 32 mutations clustered in exon 9 and exon 20, respectively. The most common mutations were E542K (6 cases) and E545K (8 cases) in exon 9, and H1047R (29 cases) in exon 20. A novel mutation, G3292T, was also found. Mutations were found less frequently in the ductal intraepithelial neoplasia 1B (DIN1B) and lower grade ductal proliferative lesions (3 of 68; 4.41%) than in ductal carcinoma in situ (14 of 57; 24.56%, P = 0.001, Chi-square test) or invasive carcinoma (29 of 108; 26.85%, P = 0.000, Chi-square test). However, there was no significant difference in the frequency of PIK3CA mutations between carcinoma in situ and invasive carcinoma (P = 0.750, Chi-square test). PIK3CA mutations mostly began to develop at the stage from the DIN1B to the carcinoma in situ (DCIS), which is a late event of breast oncogenesis. PIK3CA-mutated tumors were more frequently found in ER-a positive, PR positive, and PTEN positive tumors (P = 0.012, P = 0.004 and P = 0.004, respectively, Chi-square test). The frequency of PIK3CA gene mutation in ER+/PR+ (32/98, 32.65%) tumors was not significantly different from that in ER+/PR− (9/39, 23.08%), tested by the Chi-square test (P = 0.269). There was no significant association between PIK3CA mutations and HER2 expression status (P = 0.294, Chi-square test). 相似文献
19.
The nucleocapsid (N) protein of porcine reproductive and respiratory syndrome virus (PRRSV) is the principal component of the viral nucleocapsid and localizes to the nucleolus. Peptide sequence analysis of the N protein of several North American isolates identified two potential nuclear localization signal (NLS) sequences located at amino acids 10-13 and 41-42, which were labeled NLS-1 and NLS-2, respectively. Peptides containing NLS-1 or NLS-2 were sufficient to accumulate enhanced green fluorescent protein (EGFP) in the nucleus. The inactivation of NLS-1 by site-directed mutagenesis or the deletion of the first 14 amino acids did not affect N protein localization to the nucleolus. The substitution of key lysine residues with uncharged amino acids in NLS-2 blocked nuclear/nucleolar localization. Site-directed mutagenesis within NLS-2 identified the sequence, KKNKK, as forming the core localization domain within NLS-2. Using an in vitro pull-down assay, the N protein was able to bind importin-alpha, importin-beta nuclear transport proteins. The localization pattern of N-EGFP fusion peptides represented by a series of deletions from the C- and N-terminal ends of the N protein identified a region covering amino acids 41-72, which contained a nucleolar localization signal (NoLS) sequence. The 41-72 N peptide when fused to EGFP mimicked the nucleolar-cytoplasmic distribution of native N. These results identify a single NLS involved in the transport of N from the cytoplasm and into nucleus. An additional peptide sequence, overlapping NLS-2, is involved in the further targeting of N to the nucleolus. 相似文献
20.
Fatemeh Azadegan‐Dehkordi Reza Ahmadi Mahbobeh Koohiyan Morteza Hashemzadeh‐Chaleshtori 《Annals of human genetics》2019,83(1):1-10
Hearing loss (HL) is the most common birth defect and the most prevalent sensorineural condition worldwide. It is associated with more than 1,000 mutations in at least 90 genes. Mutations of the gap junction beta‐2 protein (GJB2) gene located in the nonsyndromic hearing loss and deafness (DFNB1) locus (chromosome 13q11‐12) are the main causes of autosomal recessive nonsyndromic hearing loss worldwide, but important differences exist between various populations. In the present article, two common mutations of the GJB2 gene are compared for ethnic‐specific allele frequency, their function, and their contribution to genetic HL in different populations. The results indicated that mutations of the GJB2 gene could have arisen during human migration. Updates on the spectrum of mutations clearly show that frequent mutations in the GJB2 gene are consistent with the founder mutation hypothesis. 相似文献