Rare diseases (Austin, Tex.)最新文献

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Loss of the tumor suppressor SMARCA4 in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) 高钙血症型卵巢小细胞癌(scoht)中肿瘤抑制因子SMARCA4的缺失

Rare diseases (Austin, Tex.)

Pub Date : 2014-01-01 DOI: 10.4161/2167549X.2014.967148

Pilar Ramos, A. Karnezis, William P. D. Hendricks, Yemin Wang, Waibhav Tembe, V. Zismann, Christophe Legendre, Winnie S. Liang, M. Russell, D. Craig, J. Farley, B. Monk, S. Anthony, A. Sekulic, H. Cunliffe, D. Huntsman, J. Trent

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare and understudied cancer with a dismal prognosis. SCCOHT's infrequency has hindered empirical study of its biology and clinical management. However, we and others have recently identified inactivating mutations in the SWI/SNF chromatin remodeling gene SMARCA4 with concomitant loss of SMARCA4 protein in the majority of SCCOHT tumors.1–4 Here we summarize these findings and report SMARCA4 status by targeted sequencing and/or immunohistochemistry (IHC) in an additional 12 SCCOHT tumors, 3 matched germlines, and the cell line SCCOHT-1. We also report the identification of a homozygous inactivating mutation in the gene SMARCB1 in one SCCOHT tumor with wild-type SMARCA4, suggesting that SMARCB1 inactivation may also play a role in the pathogenesis of SCCOHT. To date, SMARCA4 mutations and protein loss have been reported in the majority of 69 SCCOHT cases (including 2 cell lines). These data firmly establish SMARCA4 as a tumor suppressor whose loss promotes the development of SCCOHT, setting the stage for rapid advancement in the biological understanding, diagnosis, and treatment of this rare tumor type.

卵巢小细胞癌，高钙血症型(scoht)，是一种罕见的和未充分研究的癌症，预后不佳。scot的罕见性阻碍了其生物学和临床管理的实证研究。然而，我们和其他人最近发现SWI/SNF染色质重塑基因SMARCA4失活突变在大多数scot肿瘤中伴随着SMARCA4蛋白的缺失。在这里，我们总结了这些发现，并通过靶向测序和/或免疫组化(IHC)在另外12个SCCOHT肿瘤、3个匹配的种系和细胞系SCCOHT-1中报告了SMARCA4的状态。我们还报道在一个携带野生型SMARCA4的scot肿瘤中发现了SMARCB1基因的纯合失活突变，这表明SMARCB1失活也可能在scot的发病机制中发挥作用。迄今为止，在69例sccot病例(包括2个细胞系)中，大多数报告了SMARCA4突变和蛋白质丢失。这些数据牢固地确立了SMARCA4作为一种肿瘤抑制因子的地位，它的缺失促进了scot的发展，为这种罕见肿瘤类型的生物学理解、诊断和治疗的快速发展奠定了基础。

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引用次数: 43

Motor neuron degeneration in spinal and Bulbar Muscular Atrophy is a skeletal muscle-driven process: Relevance to therapy development and implications for related motor neuron diseases 脊髓和球性肌萎缩的运动神经元退化是一个骨骼肌驱动的过程:与治疗发展和相关运动神经元疾病的意义

Rare diseases (Austin, Tex.)

Pub Date : 2014-01-01 DOI: 10.4161/2167549X.2014.962402

Constanza J. Cortes, A. L. La Spada

Non-cell autonomous degeneration has arisen as an important mechanism in neurodegenerative disorders. Using a novel line of BAC androgen receptor (AR) transgenic mice with a floxed transgene (BAC fxAR121), we uncovered a key role for skeletal muscle in X-linked Spinal and Bulbar Muscular Atrophy (SBMA), a motor neuronopathy caused by a polyglutamine expansion in exon 1 of the AR gene. By excising the mutant AR transgene from muscle only, we achieved complete rescue of neuromuscular phenotypes in these mice, despite retaining strong CNS expression. Furthermore, we delivered an antisense oligonucleotide (ASO) directed against the human AR transgene by peripheral injection, and documented that peripheral ASO delivery could rescue muscle weakness and premature death in BAC fxAR121 mice. Our results reveal a crucial role for skeletal muscle in SBMA disease pathogenesis, and offer an appealing avenue for therapy development for SBMA and perhaps also for related motor neuron diseases.

非细胞自主变性已成为神经退行性疾病的重要机制。利用一种新型的BAC雄激素受体(AR)转基因小鼠(BAC fxAR121)，我们发现了骨骼肌在x连锁脊髓和球性肌萎缩症(SBMA)中的关键作用，SBMA是一种由AR基因外显子1的聚谷氨酰胺扩增引起的运动神经病变。通过仅从肌肉中切除突变AR转基因，我们在这些小鼠中实现了神经肌肉表型的完全恢复，尽管保留了强中枢神经系统表达。此外，我们通过外周注射给药了一种针对人AR转基因的反义寡核苷酸(ASO)，并证明外周给药ASO可以挽救BAC fxAR121小鼠的肌肉无力和过早死亡。我们的研究结果揭示了骨骼肌在SBMA疾病发病机制中的关键作用，并为SBMA以及相关运动神经元疾病的治疗发展提供了一条有吸引力的途径。

引用次数: 4

Unraveling the mechanism by which TRPV4 mutations cause skeletal dysplasias 揭示TRPV4突变导致骨骼发育不良的机制

Rare diseases (Austin, Tex.)

Pub Date : 2014-01-01 DOI: 10.4161/2167549X.2014.962971

H. Leddy, A. McNulty, F. Guilak, W. Liedtke

Transient Receptor Potential Vanilloid 4 (TRPV4) is a mechano- and osmosensitive cation channel that is highly expressed in chondrocytes, the cells in cartilage. A large number of mutations in TRPV4 have been linked to skeletal dysplasias, and the goal of this addendum is to shed light on the mechanisms by which mutations in TRPV4 can cause skeletal dysplasias by focusing on 3 recent publications. These papers suggest that skeletal dysplasia-causing TRPV4 mutations reprogram chondrocytes to increase follistatin production, which inhibits BMP signaling, thus slowing the process of endochondral ossification and leading to skeletal dysplasia. In spite of these important advances in our understanding of the disease mechanism, much remains to be elucidated. Nonetheless, these new data suggest that inhibiting aberrant TRPV4 activity in the cartilage may be a promising direction for therapeutic intervention.

瞬时受体电位香草样蛋白4 (TRPV4)是一种机械和渗透敏感的阳离子通道，在软骨细胞中高度表达。大量TRPV4突变与骨骼发育不良有关，本附录的目的是通过关注最近发表的3篇文章，阐明TRPV4突变导致骨骼发育不良的机制。这些研究表明，导致骨骼发育不良的TRPV4突变会对软骨细胞进行重编程，从而增加卵泡素的产生，从而抑制BMP信号，从而减缓软骨内骨化过程，导致骨骼发育不良。尽管我们对疾病机制的理解取得了这些重要进展，但仍有许多有待阐明。尽管如此，这些新数据表明，抑制软骨中异常的TRPV4活性可能是治疗干预的一个有希望的方向。

引用次数: 23

The methyl binding domain containing protein MBD5 is a transcriptional regulator responsible for 2q23.1 deletion syndrome 含有MBD5蛋白的甲基结合域是2q23.1缺失综合征的转录调控因子

Rare diseases (Austin, Tex.)

Pub Date : 2014-01-01 DOI: 10.4161/2167549X.2014.967151

K. Walz, Juan I. Young

2Iq23.1 microdeletion syndrome is a recently described rare disease that includes intellectual disability, motor delay, autistic-like behaviors, and craniofacial abnormalities. Dosage insufficiency of the methyl-CpG-binding domain protein 5 (MBD5) gene was suggested as the genetic cause, since all the described patients carry a partial or total heterozygous deletion of MBD5. We reported the generation and characterization of a mouse model with haploinsufficiency for Mbd5 that confirmed this hypothesis. As in human 2q23.1 microdeletion syndrome, the MBD5+/GT mouse model exhibited abnormal social behavior, cognitive impairment, and motor and craniofacial abnormalities, supporting a causal role for MBD5 in 2q23.1 microdeletion syndrome. The use of mouse neuronal cultures uncovered a deficiency in neurite outgrowth, suggesting the participation of MBD5 in neuronal processes. The study of the MBD5+/GT mouse advanced our understanding of the abnormal brain development associated with behavioral and cognitive symptoms.

2Iq23.1微缺失综合征是一种最近发现的罕见疾病，包括智力残疾、运动迟缓、自闭症样行为和颅面异常。甲基cpg结合结构域蛋白5 (MBD5)基因剂量不足被认为是遗传原因，因为所有描述的患者都携带部分或全部MBD5杂合缺失。我们报道了Mbd5单倍不足小鼠模型的产生和表征，证实了这一假设。与人类2q23.1微缺失综合征一样，MBD5+/GT小鼠模型表现出异常的社交行为、认知障碍、运动和颅面异常，支持MBD5在2q23.1微缺失综合征中的因果作用。使用小鼠神经元培养发现了神经突生长缺陷，提示MBD5参与神经元过程。对MBD5+/GT小鼠的研究促进了我们对与行为和认知症状相关的大脑异常发育的理解。

引用次数: 3

Gene therapy for Wiskott-Aldrich Syndrome—Long-term reconstitution and clinical benefits, but increased risk for leukemogenesis Wiskott-Aldrich综合征的基因治疗-长期重建和临床益处，但增加了白血病发生的风险

Rare diseases (Austin, Tex.)

Pub Date : 2014-01-01 DOI: 10.4161/21675511.2014.947749

C. Braun, Maximilian Witzel, A. Paruzynski, K. Boztug, C. von Kalle, M. Schmidt, C. Klein

Wiskott-Aldrich-Syndrome (WAS) is a rare X-linked recessive disease caused by mutations of the WAS gene. It is characterized by immunodeficiency, autoimmunity, low numbers of small platelets (microthrombocytopenia) and a high risk of cancer, especially B cell lymphoma and leukemia.

Wiskott-Aldrich-Syndrome (WAS)是一种罕见的由WAS基因突变引起的x连锁隐性疾病。其特点是免疫缺陷，自身免疫，小血小板(微血小板减少症)数量少，癌症风险高，特别是B细胞淋巴瘤和白血病。

引用次数: 21

Spondylocheirodysplastic Ehlers-Danlos syndrome (SCD-EDS) and the mutant zinc transporter ZIP13 脊椎骨发育不良综合征(SCD-EDS)和突变型锌转运蛋白ZIP13

Rare diseases (Austin, Tex.)

Pub Date : 2014-01-01 DOI: 10.4161/21675511.2014.974982

Bum-Ho Bin, Shintaro Hojyo, Tae Ryong Lee, T. Fukada

The zinc transporter protein ZIP13 plays crucial roles in bone, tooth, and connective tissue development, and its dysfunction is responsible for the spondylocheirodysplastic form of Ehlers-Danlos syndrome (SCD-EDS, OMIM 612350). We recently reported that the pathogenic mutations in ZIP13 reduce its functional protein level by accelerating the protein degradation via the VCP-linked ubiquitin proteasome pathway, resulting in the disturbance of intracellular zinc homeostasis that appears to contribute to SCD-EDS pathogenesis. Finally, we implicate that possible therapeutic approaches for SCD-EDS would be based on regulating the degradation of the pathogenic mutant ZIP13 proteins.

锌转运蛋白ZIP13在骨骼、牙齿和结缔组织发育中起着至关重要的作用，其功能障碍是导致ehers - danlos综合征(SCD-EDS, OMIM 612350)脊椎发育不良的原因。我们最近报道，ZIP13的致病性突变通过vcp连接的泛素蛋白酶体途径加速蛋白质降解，从而降低其功能蛋白水平，导致细胞内锌稳态紊乱，这似乎有助于SCD-EDS的发病。最后，我们认为SCD-EDS可能的治疗方法是基于调节致病突变体ZIP13蛋白的降解。

引用次数: 24

TDP-43-The key to understanding amyotrophic lateral sclerosis. tdp -43-了解肌萎缩侧索硬化的关键。

Rare diseases (Austin, Tex.)

Pub Date : 2014-01-01 DOI: 10.4161/21675511.2014.944443

Zuoshang Xu, Chunxing Yang

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes motor neuron degeneration leading to progressive muscle atrophy, weakness, paralysis and death. The majority of ALS (>95%) shows intracellular aggregation of transactive response DNA binding protein (TDP-43) as a prominent pathological feature. TDP-43 is normally a nuclear protein. In ALS, TDP-43 accumulates and aggregates in the cytoplasm (thus forming TDP-43 proteinopathy) and is depleted from the nucleus in CNS cells, including motor neurons and glia. While TDP-43 aggregation can harm cells through a gain of toxicity, it can also cause a loss of TDP-43 function in conjunction with its nuclear depletion. TDP-43 regulates its own expression to maintain itself at a constant level. Perturbation of this level by either increasing or decreasing TDP-43 in animal models leads to neurodegeneration and ALS phenotypes. The evidence supports the hypothesis that TDP-43 dysfunction is a critical driver of neurodegeneration in the vast majority of ALS cases.

肌萎缩性侧索硬化症(ALS)是一种致命的神经退行性疾病，引起运动神经元变性，导致进行性肌肉萎缩、无力、瘫痪和死亡。大多数ALS(>95%)表现为细胞内反应性DNA结合蛋白(TDP-43)聚集，这是一个突出的病理特征。TDP-43通常是一个核蛋白。在ALS中，TDP-43在细胞质中积累和聚集(从而形成TDP-43蛋白病)，并在包括运动神经元和神经胶质在内的中枢神经系统细胞中从细胞核中耗尽。虽然TDP-43聚集可以通过毒性的增加来损害细胞，但它也可以导致TDP-43功能的丧失及其核耗竭。TDP-43调节自身表达，使自身维持在恒定水平。在动物模型中，通过增加或减少TDP-43水平的扰动会导致神经退行性变和ALS表型。证据支持TDP-43功能障碍是绝大多数ALS病例神经退行性变的关键驱动因素的假设。

引用次数: 17

Muscle-specific microRNAs as biomarkers of Duchenne Muscular Dystrophy progression and response to therapies 肌肉特异性microrna作为杜氏肌营养不良进展和对治疗反应的生物标志物

Rare diseases (Austin, Tex.)

Pub Date : 2014-01-01 DOI: 10.4161/21675511.2014.974969

Lorenzo Giordani, M. Sandonà, A. Rotini, P. L. Puri, S. Consalvi, V. Saccone

Recent studies have revealed the contribution of fibro-adipogenic progenitors (FAPs) to the pathogenesis and progression of Duchenne Muscular Dystrophy (DMD). While FAPs direct compensatory regeneration at early stages of disease, as the disease progresses they contribute to the progressive replacement of contractile myofibers with fibrotic scars and fatty infiltration. Using the mouse model of DMD – the mdx mice - we have recently reported that FAPs mediate the ability of HDAC inhibitors (HDACi) to promote muscle regeneration and prevent fibro-adipogenic degeneration at early stages of disease. This effect is mediated by the induction of myomiRs that, in turn, target the SWI/SNF components BAF60A and B, thereby favoring the formation of BAF60C-based SWI/SNF complex, which directs the switch from the fibro-adipogenic to the myogenic lineage. Here we show direct evidence of induction of miR-206 and BAF60C, and reduction of BAF60A, in FAPs isolated from mdx muscles exposed to the HDACi Trichostatin A (TSA). We also discuss how increased expression of myomiRs in dystrophic muscles can be integrated with circulating myomiRs to provide accurate biomarkers of disease progression and response to treatment.

最近的研究揭示了纤维脂肪源性祖细胞(FAPs)在杜氏肌营养不良症(DMD)的发病和进展中的作用。虽然FAPs在疾病的早期阶段直接代偿性再生，但随着疾病的进展，它们会导致具有纤维化疤痕和脂肪浸润的可收缩肌纤维的逐渐替代。利用DMD小鼠模型mdx小鼠，我们最近报道了FAPs介导HDAC抑制剂(HDACi)在疾病早期促进肌肉再生和防止纤维脂肪变性的能力。这种作用是由myomir的诱导介导的，myomir反过来靶向SWI/SNF成分BAF60A和B，从而有利于基于baf60c的SWI/SNF复合物的形成，从而指导从纤维脂肪生成到肌源性谱系的转换。在这里，我们展示了直接的证据，在暴露于hdac Trichostatin A (TSA)的mdx肌肉分离的FAPs中，诱导miR-206和BAF60C，并减少BAF60A。我们还讨论了肌营养不良肌肉中肌球蛋白表达的增加如何与循环肌球蛋白相结合，以提供疾病进展和对治疗反应的准确生物标志物。

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引用次数: 17

Impaired striatal function in Huntington's disease is due to aberrant p75NTR signaling 亨廷顿氏病纹状体功能受损是由于p75NTR信号异常

Rare diseases (Austin, Tex.)

Pub Date : 2014-01-01 DOI: 10.4161/2167549X.2014.968482

Joshua L. Plotkin, D. Surmeier

Huntington's disease (HD) is a rare genetic neurodegenerative disorder for which there is currently no cure. Early hyperkinetic motor symptoms are consistent with reduced activity of indirect pathway striatal projection neurons (iSPNs) responsible for suppression of unwanted actions. Our recent work suggests that one of the factors contributing to this deficit is impaired brain-derived neurotrophic factor (BDNF) signaling that regulates the strength of iSPN excitatory synapses. Specifically, we found that BDNF-dependent corticostriatal synaptic long-term potentiation (LTP) was lost in iSPNs from 2 genetic models of HD, just as they began to robustly manifest motor symptoms. This deficit was not attributable to problems in BDNF production, delivery or receptor binding. Rather, the plasticity deficit stemmed from enhanced signaling through p75 neurotrophin receptors (p75NTRs) and the phosphatase and tensin homolog (PTEN), leading to antagonism of intracellular TrkBR cascades and LTP. This study suggests HD therapeutics should target p75NTR signaling, not TrkBR.

亨廷顿氏病(HD)是一种罕见的遗传性神经退行性疾病，目前尚无治愈方法。早期多动运动症状与负责抑制不良行为的间接通路纹状体投射神经元(ispn)活性降低一致。我们最近的研究表明，导致这种缺陷的因素之一是调节iSPN兴奋性突触强度的脑源性神经营养因子(BDNF)信号传导受损。具体来说，我们发现bdnf依赖性皮质纹状体突触长期增强(LTP)在2种HD遗传模型的ispn中丢失，就在他们开始强烈表现出运动症状时。这种缺陷不能归因于BDNF的产生、传递或受体结合的问题。相反，可塑性缺陷源于通过p75神经营养因子受体(p75NTRs)和磷酸酶和紧张素同源物(PTEN)增强的信号传导，导致细胞内TrkBR级联反应和LTP的拮抗。这项研究表明，HD治疗应该针对p75NTR信号，而不是TrkBR。

引用次数: 9

Alkaptonuria. 尿黑酸尿。

Rare diseases (Austin, Tex.)

Pub Date : 2013-12-18 eCollection Date: 2013-01-01 DOI: 10.4161/rdis.27475

Jemma B Mistry, Marwan Bukhari, Adam M Taylor

Alkaptonuria (AKU) is a rare disorder of autosomal recessive inheritance. It is caused by a mutation in a gene that results in the accumulation of homogentisic acid (HGA). Characteristically, the excess HGA means sufferers pass dark urine, which upon standing turns black. This is a feature present from birth. Over time patients develop other manifestations of AKU, due to deposition of HGA in collagenous tissues, namely ochronosis and ochronotic osteoarthropathy. Although this condition does not reduce life expectancy, it significantly affects quality of life. The natural history of this condition is becoming better understood, despite gaps in knowledge. Clinical assessment of the condition has also improved along with the development of a potentially disease-modifying therapy. Furthermore, recent developments in AKU research have led to new understanding of the disease, and further study of the AKU arthropathy has the potential to influence therapy in the management of osteoarthritis.

尿尿症(AKU)是一种罕见的常染色体隐性遗传疾病。它是由基因突变引起的，导致均质酸(HGA)的积累。典型的是，过量的HGA意味着患者排出的尿液颜色较深，站立后会变成黑色。这是一种与生俱来的特征。随着时间的推移，由于HGA在胶原组织中的沉积，患者出现AKU的其他表现，即衰老病和衰老性骨关节病。虽然这种情况不会降低预期寿命，但它会显著影响生活质量。尽管在知识上存在差距，但人们对这种疾病的自然史已经有了更好的了解。随着一种潜在的疾病改善疗法的发展，这种疾病的临床评估也得到了改善。此外，AKU研究的最新进展使人们对该疾病有了新的认识，对AKU关节病的进一步研究有可能影响骨关节炎的治疗。

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