SIFD

SIFD
  • 文章类型: Journal Article
    线粒体疾病是由线粒体功能失调引起的一组异质性疾病。有趣的是,大部分线粒体疾病是由与tRNA代谢相关的基因缺陷引起的。我们最近发现tRNA核苷酸转移酶1(TRNT1)的部分功能丧失突变,编码对修饰核和线粒体tRNAs至关重要的CCA添加酶的核基因,引起多系统和临床异质性疾病,称为SIFD(具有B细胞免疫缺陷的铁粒母细胞性贫血,周期性发烧,和发育迟缓;SIFD)。然而,目前尚不清楚TRNT1等一般和必需蛋白的突变如何导致具有如此广泛的临床症状和组织受累的疾病.利用生化,cell,和质谱方法,我们证明TRNT1缺乏与对氧化应激的敏感性有关,这是由于加剧,血管生成素依赖性的tRNA裂解。此外,TRNT1水平降低导致真核翻译起始因子2亚基α(eIF2α)磷酸化,增加活性氧(ROS)的产生,以及不同蛋白质丰度的变化。我们的数据表明,观察到的可变SIFD表型可能是由于tRNA成熟和丰度的失调,这反过来对不同蛋白质的翻译产生负面影响。
    Mitochondrial diseases are a group of heterogeneous disorders caused by dysfunctional mitochondria. Interestingly, a large proportion of mitochondrial diseases are caused by defects in genes associated with tRNA metabolism. We recently discovered that partial loss-of-function mutations in tRNA Nucleotidyl Transferase 1 (TRNT1), the nuclear gene encoding the CCA-adding enzyme essential for modifying both nuclear and mitochondrial tRNAs, causes a multisystemic and clinically heterogenous disease termed SIFD (sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay; SIFD). However, it is not clear how mutations in a general and essential protein like TRNT1 cause disease with such clinically broad but unique symptomatology and tissue involvement. Using biochemical, cell, and mass spectrometry approaches, we demonstrate that TRNT1 deficiency is associated with sensitivity to oxidative stress, which is due to exacerbated, angiogenin-dependent cleavage of tRNAs. Furthermore, reduced levels of TRNT1 lead to phosphorylation of Eukaryotic Translation Initiation Factor 2 Subunit Alpha (eIF2α), increased reactive oxygen species (ROS) production, and changes in the abundance of distinct proteins. Our data suggest that the observed variable SIFD phenotypes are likely due to dysregulation of tRNA maturation and abundance, which in turn negatively affects the translation of distinct proteins.
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  • 文章类型: Journal Article
    目标:铁粒幼细胞性贫血,免疫缺陷,周期性发烧,发育迟缓(SIFD)是由tRNA核苷酸转移酶1(TRNT1)的双等位基因功能丧失变体引起的常染色体隐性综合征。缺乏治疗SIFD的有效方法。我们确定了TRNT1中的两个新突变和SIFD的有效和新颖疗法。
    方法:我们回顾性总结了来自不同家庭的两名SIFD患者的临床记录,并回顾了所有已发表的SIFD病例。
    结果:两名患者都有周期性发热,发育迟缓,皮疹,小细胞性贫血,和B细胞淋巴细胞减少与感染。患者1的全外显子组测序鉴定了先前未报告的TRNT1纯合突变(c.706G>A/p。Glu236Lys)。他接受了静脉注射免疫球蛋白(IVIG)替代治疗和抗生素,但在1岁时死亡。患者2的基因检测显示复合杂合突变(c.907C>G/p。Gln303Glu和c.88A>G/p。Met30Val)在TRNT1中,前者是一种新的突变。阿达木单抗治疗和IVIG替代治疗后的第一个月,周期性发热得到控制。但在第二个月复发。停用阿达木单抗并替换为沙利度胺,有效控制周期性发热并使炎症标志物正常化。对报告病例的回顾性分析显示,69例SIFD患者携带46个突变。男女比例为1:1,平均发病年龄为3.0个月。SIFD患者最常见的临床表现是小细胞性贫血(82.6%),低球蛋白血症/B细胞淋巴细胞减少(75.4%),周期性发热(66.7%),和发育迟缓(60.0%)。除了典型的四联症,SIFD具有涉及多个系统的几种异质症状。皮质类固醇,免疫抑制剂,和anakinra疗效低,而依那西普抑制了发热并改善了贫血。骨髓移植可用于治疗严重的SIFD,但风险很高。总的来说,28.2%(20/71)的报告患者死亡,主要是因为多器官衰竭。位于外显子1-内含子5的双等位基因突变导致更严重的表型和更高的死亡率。此外,15.5%(11/71)的患者存活到成年。五名患者的症状可以自发缓解。
    结论:沙利度胺可以控制SIFD的炎症,是一种新的SIFD治疗方法。
    Sideroblastic anemia, immunodeficiency, periodic fevers, and developmental delay (SIFD) is an autosomal recessive syndrome caused by biallelic loss-of-function variant of tRNA nucleotidyl transferase 1 (TRNT1). Efficacious methods to treat SIFD are lacking. We identified two novel mutations in TRNT1 and an efficacious and novel therapy for SIFD.
    We retrospectively summarized the clinical records of two patients with SIFD from different families and reviewed all published cases of SIFD.
    Both patients had periodic fever, developmental delay, rash, microcytic anemia, and B cell lymphopenia with infections. Whole-exome sequencing of patient 1 identified a previously unreported homozygous mutation of TRNT1 (c.706G > A/p.Glu236Lys). He received intravenous immunoglobulin (IVIG) replacement and antibiotics, but died at 1 year of age. Gene testing in patient 2 revealed compound heterozygous mutations (c.907C > G/p.Gln303Glu and c.88A > G/p.Met30Val) in TRNT1, the former of which is a novel mutation. Periodic fever was controlled in the first month after adalimumab therapy and IVIG replacement, but recurred in the second month. Adalimumab was discontinued and replaced with thalidomide, which controlled the periodic fever and normalized inflammatory markers effectively. A retrospective analysis of reported cases revealed 69 patients with SIFD carrying 46 mutations. The male: female ratio was 1: 1, and the mean age of onset was 3.0 months. The most common clinical manifestations in patients with SIFD were microcytic anemia (82.6%), hypogammaglobulinemia/B cell lymphopenia (75.4%), periodic fever (66.7%), and developmental delay (60.0%). In addition to the typical tetralogy, SIFD features several heterogeneous symptoms involving multiple systems. Corticosteroids, immunosuppressants, and anakinra have low efficacy, whereas etanercept suppressed fever and improved anemia in reports. Bone-marrow transplantation can be used to treat severe SIFD, but carries a high risk. In total, 28.2% (20/71) of reported patients died, mainly because of multi-organ failure. Biallelic mutations located in exon1-intron5 lead to more severe phenotypes and higher mortality. Furthermore, 15.5% (11/71) patients survived to adulthood. The symptoms could be resolved spontaneously in five patients.
    Thalidomide can control the inflammation of SIFD and represents a new treatment for SIFD.
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  • 文章类型: Systematic Review
    目的:铁粒幼细胞贫血伴B细胞免疫缺陷,周期性发热和发育迟缓(SIFD)综合征是一种罕见的自身炎症性多系统疾病。我们对SIFD综合征的可用临床和治疗方面进行了系统评价。
    方法:根据PRISMA方法进行的系统综述,包括2021年7月30日之前在Pubmed和EMBASE数据库中发表的所有文章,已执行。
    结果:搜索确定了29篇出版物,描述了58名独特患者。迄今为止,已经报道了41种独特的突变。发病非常早,中位年龄为4个月(范围0-252个月)。最常见的表现是血液病,如小细胞性贫血或铁粒幼细胞性贫血(55/58),反复发烧(52/58),神经异常(48/58),免疫异常,特别是体液免疫缺陷(48/58),胃肠道体征和症状(38/58),眼病如白内障和视网膜色素变性(27/58),未能茁壮成长(26/58),粘膜皮肤受累(29/58),感音神经性耳聋(19/58)等。迄今为止,19例(35.85%)因病程(16例)和造血干细胞移植并发症(3例)死亡。抗TNFα和造血干细胞移植(HCST)的使用正在极大地改变这种疾病的自然史。
    结论:SIFD综合征是出现反复发热的儿童的一种新实体,贫血,B细胞免疫缺陷和神经发育迟缓。迄今为止,缺乏治疗指南,但抗TNFα治疗和/或HCST治疗具有吸引力,可能会改变该综合征的临床病程.
    Sideroblastic anaemia with B-cell immunodeficiency, periodic fever and developmental delay (SIFD) syndrome is a novel rare autoinflammatory multisystem disorder. We performed a systematic review of the available clinical and therapeutics aspects of the SIFD syndrome.
    A systematic review according to PRISMA approach, including all articles published before the 30th of July 2021 in Pubmed and EMBASE database, was performed.
    The search identified 29 publications describing 58 unique patients. To date, 41 unique mutations have been reported. Onset of disease is very early with a median age of 4 months (range 0-252 months). The most frequent manifestations are haematologic such as microcytic anaemia or sideroblastic anaemia (55/58), recurrent fever (52/58), neurologic abnormalities (48/58), immunologic abnormalities in particular a humoral immunodeficiency (48/58), gastrointestinal signs and symptoms (38/58), eye diseases as cataract and retinitis pigmentosa (27/58), failure to thrive (26/58), mucocutaneous involvement (29/58), sensorineural deafness (19/58) and others. To date, 19 patients (35.85%) died because of disease course (16) and complications of hematopoietic cell stems transplantation (3). The use of anti-TNFα and hematopoietic cell stems transplantation (HCST) is dramatically changing the natural history of this disease.
    SIFD syndrome is a novel entity to consider in a child presenting with recurrent fever, anaemia, B-cell immunodeficiency and neurodevelopmental delay. To date, therapeutic guidelines are lacking but anti-TNFα treatment and/or HCST are attractive and might modify the clinical course of this syndrome.
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  • 文章类型: Journal Article
    铁粒幼细胞性贫血伴B细胞免疫缺陷,周期性发烧,发育迟缓(SIFD)综合征是一种严重的常染色体隐性遗传病。到目前为止,全世界已报告<40例,中国只报告了一例。SIFD的主要临床特征是铁粒成细胞或小红细胞性贫血,免疫缺陷,和反复发作的炎症.这里,我们描述了来自中国的两个不相关的SIFD病例,这些病例具有不同的临床表现和轻度症状。患者1在3.5岁时住院,原因是持续性关节肿胀,并进行了多个关节积液的成像。患者2在12岁时因下肢反复出现皮疹和口腔溃疡而住院。使用基因检测检测到SIFD,在病例1和2中分别揭示了TRNT1中的以下复合杂合变体:c.88A>G/c.363G>T和c.302T>C/c.1234cC>T。对HGMD数据库的搜索显示这些变体都是新颖的。分子动力学模拟表明,错义变体c.363G>T和c.302T>C会引起蛋白质结构的变化,从而影响蛋白质功能。最后,通过文献回顾,我们发现SIFD病例的死亡率约为44%(14/32),大约79%的死亡个体携带热点突变c.668T>C。此外,非编码区变异在死亡患者中明显比在幸存者中更常见.我们的病例进一步扩展了对SIFD表型和变异谱的现有知识,并表明基因组诊断对于该疾病的分层临床管理具有重要意义。
    Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) syndrome is a serious autosomal recessive genetic disease. So far, <40 cases have been reported worldwide, and only one case has been reported in China. The main clinical features of SIFD are sideroblastic or microcytic anemia, immune deficiency, and recurrent episodes of inflammation. Here, we describe two unrelated cases of SIFD from China with different clinical manifestations and mild symptoms. Patient 1 was hospitalized at the age of 3.5 years due to persistent joint swelling with imaging of multiple joint effusions. Patient 2 was hospitalized at the age of 12 years due to repeated rashes on both lower limbs and oral ulcers. SIFD was detected using gene testing, which revealed the following compound heterozygous variants in TRNT1 in cases 1 and 2, respectively: c.88A > G/c.363G > T and c.302 T > C/c.1234cC > T. Searches of the HGMD databases revealed that these variants were all novel. Molecular dynamics simulations revealed that the missense variants c.363G > T and c.302 T > C would cause changes in protein structure and thus affect protein function. Finally, through literature reviewing, we found that the mortality in cases of SIFD was approximately 44% (14/32), and about 79% of individuals who died carried the hot-spot mutation c.668 T > C. Moreover, variants in the non-coding region were significantly more common among patients who died than among survivors. Our cases further expand the existing knowledge of the phenotype and variation spectrums of SIFD and suggest that genomic diagnosis is valuable for the hierarchical clinical management of this disease.
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  • 文章类型: Journal Article
    Mutations in the gene encoding tRNA nucleotidyltransferase 1 (TRNT1) are associated with heterogeneous phenotypes and multisystem involvement of variable severity and progression. Immunodeficiency and inflammation are recurrent-associated features. The use of cytokine inhibitors in suppressing the inflammatory phenotype has been recently reported, with a 3-year follow-up for patients treated with Etanercept. We report on two unrelated patients sharing the same clinical condition, who had been referred to our Pediatric Rheumatology Unit because of recurrent fever associated with cutaneous lesions and increased levels of inflammatory markers since their first months of life. Whole exome sequencing allowed to identify compound heterozygosity for functionally relevant variants in TRNT1 as the only molecular event shared by the two patients. Both patients have been treated with Etanercept during 11 years, documenting normalization of inflammatory indexes and resolution of recurrent fever and associated symptoms. This is the longest follow-up assessment of Etanercept treatment in patients with TRNT1 mutations. Our findings confirm efficacy and safety of the treatment. Key Points • Mutations in TRNT1 have been associated with phenotypic heterogeneity. • We report on two patients with early-onset autoinflammatory syndrome. • Whole exome sequencing led to reveal compound heterozygosity for two variants in TRNT1 in both patients. • The patients were successfully treated with Etanercept for more than 10 years, the longest follow-up described in literature.
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  • 文章类型: Journal Article
    Mutations in the gene encoding transfer RNA (tRNA) nucleotidyltransferase, CCA-adding 1 (TRNT1), an enzyme essential for the synthesis of the 3\'-terminal CCA sequence in tRNA molecules, are associated with a rare syndrome of congenital sideroblastic anemia, B cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Clinical manifestations and immunological phenotypes were assessed in a Chinese patient with novel compound heterozygous mutations in TRNT1. The patient required multiple hospitalizations starting at the age of 2 years for recurrent fevers without an infective cause. During the febrile episode, the patient was found to have microcytic hypochromic anemia, B cell lymphopenia, and hypogammaglobulinemia. Targeted gene sequencing identified novel compound heterozygous mutations in the TRNT1 gene (c.525delT, p.Leu176X; c.938T>C, p.Leu313Ser). Immunophenotyping revealed increased CD8+ T cells, CD4+ terminally differentiated effector memory helper T lymphocytes (CD4 TEMRA), and CD4+ effector memory lymphocytes (CD4 EM). Analysis of CD4+ T subsets identified decreased T follicular helper cells (Tfh) with a biased phenotype to Th2-like cells. The patient also showed a lower percentage of switched memory B (smB) cells. Additionally, defects in the cytotoxicity of the patient\'s NK and γδT cells were shown by CD107alpha expression. In conclusion, T RNT1 mutations may lead to multiple immune abnormality especially humoral and cytotoxicity defects, which indicate that SIFD is not only suffered \'Predominantly antibody deficiencies\' in IUIS classification system, and further studies are needed to understand the pathogenesis of immunodeficiency in these patients.
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  • 文章类型: Case Reports
    Mutation in the gene encoding tRNA nucleotidyl transferase, CCA-adding 1 (TRNT1), an enzyme essential for the synthesis of the 3\'-terminal CCA sequence in tRNA molecules, results in a disorder that features sideroblastic anemia, B-cell immunodeficiency, periodic fever, and developmental delay. Mutations in TRNT1 are also linked to phenotypes including retinitis pigmentosa, cataracts, and cardiomyopathy. To date, it has remained unclear how defective TRNT1 is linked to B-cell deficiency. Here we report the case of a 12-year-old boy without sideroblastic anemia who harbors novel compound heterozygous mutations in TRNT1. Immunophenotypic analysis revealed severely decreased levels of B cells and follicular helper T cells. In the bone marrow, B-cell maturation stopped at the CD19+CD10+CD20+/- pre-B-cell stage. Severe combined immunodeficiency mice transplanted with bone marrow hematopoietic stem cells from the patient showed largely normal B-cell engraftment and differentiation in the bone marrow and periphery at 24 weeks post-transplantation, comparable to those in mouse transplanted with healthy hematopoietic stem cells. Biochemical analysis revealed augmented endoplasmic reticulum (ER) stress response in activated T cells. Peripheral B-cell deficiency of TRNT1 deficiency may be associated with augmented ER stress in immature B cells in the bone marrow.
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  • 文章类型: Journal Article
    Mutations in the human TRNT1 gene encoding tRNA nucleotidyltransferase (tRNA-NT), an essential enzyme responsible for addition of the CCA (cytidine-cytidine-adenosine) sequence to the 3\'-termini of tRNAs, have been linked to disease phenotypes including congenital sideroblastic anemia with B-cell immunodeficiency, periodic fevers and developmental delay (SIFD) or retinitis pigmentosa with erythrocyte microcytosis. The effects of these disease-linked mutations on the structure and function of tRNA-NT have not been explored. Here we use biochemical and biophysical approaches to study how five SIFD-linked amino acid substitutions (T154I, M158V, L166S, R190I and I223T), residing in the N-terminal head and neck domains of the enzyme, affect the structure and activity of human tRNA-NT in vitro. Our data suggest that the SIFD phenotype is linked to poor stability of the T154I and L166S variant proteins, and to a combination of reduced stability and altered catalytic efficiency in the M158 V, R190I and I223T variants.
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  • 文章类型: Journal Article
    TRNT1 (CCA-adding transfer RNA nucleotidyl transferase) enzyme deficiency is a new metabolic disease caused by defective post-transcriptional modification of mitochondrial and cytosolic transfer RNAs (tRNAs).
    We investigated four patients from two families with infantile-onset cyclical, aseptic febrile episodes with vomiting and diarrhoea, global electrolyte imbalance during these episodes, sideroblastic anaemia, B lymphocyte immunodeficiency, retinitis pigmentosa, hepatosplenomegaly, exocrine pancreatic insufficiency and renal tubulopathy. Other clinical features found in children include sensorineural deafness, cerebellar atrophy, brittle hair, partial villous atrophy and nephrocalcinosis. Whole exome sequencing and bioinformatic filtering were utilised to identify recessive compound heterozygous TRNT1 mutations (missense mutation c.668T>C, p.Ile223Thr and a novel splice mutation c.342+5G>T) segregating with disease in the first family. The second family was found to have a homozygous TRNT1 mutation (c.569G>T), p.Arg190Ile, (previously published). We found normal mitochondrial translation products using passage matched controls and functional perturbation of 3\' CCA addition to mitochondrial tRNAs (tRNA(Cys), tRNA(LeuUUR) and tRNA(His)) in fibroblasts from two patients, demonstrating a pathomechanism affecting the CCA addition to mt-tRNAs. Acute management of these patients included transfusion for anaemia, fluid and electrolyte replacement and immunoglobulin therapy. We also describe three-year follow-up findings after treatment by bone marrow transplantation in one patient, with resolution of fever and reversal of the abnormal metabolic profile.
    Our report highlights that TRNT1 mutations cause a spectrum of disease ranging from a childhood-onset complex disease with manifestations in most organs to an adult-onset isolated retinitis pigmentosa presentation. Systematic review of all TRNT1 cases and mutations reported to date revealed a distinctive phenotypic spectrum and metabolic and other investigative findings, which will facilitate rapid clinical recognition of future cases.
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  • 文章类型: Journal Article
    SIFD(铁粒幼细胞性贫血伴B细胞免疫缺陷,周期性发烧,和发育迟缓)是一种与B细胞免疫缺陷相关的先天性铁粒母细胞性贫血的新形式,周期性发烧,和由CCA添加酶TRNT1突变引起的发育延迟,但确切的分子病理生理学尚不清楚。
    我们显示,与对照细胞相比,患者来源的成纤维细胞中的致病突变不影响TRNT1的亚细胞定位,并且没有显示出总体形态差异。细胞呼吸和氧化磷酸化(OXPHOS)复合物的分析表明,患者细胞的基础和最大呼吸速率均降低。这可能归因于观察到的OXPHOS复合物的选择蛋白质的丰度降低。
    我们的数据为SIFD的细胞病理生理学提供了进一步的见解。
    SIFD (Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay) is a novel form of congenital sideroblastic anemia associated with B-cell immunodeficiency, periodic fevers, and developmental delay caused by mutations in the CCA-adding enzyme TRNT1, but the precise molecular pathophysiology is not known.
    We show that the disease causing mutations in patient-derived fibroblasts do not affect subcellular localization of TRNT1 and show no gross morphological differences when compared to control cells. Analysis of cellular respiration and oxidative phosphorylation (OXPHOS) complexes demonstrates that both basal and maximal respiration rates are decreased in patient cells, which may be attributed to an observed decrease in the abundance of select proteins of the OXPHOS complexes.
    Our data provides further insight into cellular pathophysiology of SIFD.
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