Bisatellited dicentric chromosome: A report on a case with karyotype 47,XY,+psu dic(22)t(22;22)(22pter→cen→22q11::22q11→22pter)

Summary A 12-year-old boy with mental retardation and congenital anomalies was found to have a supernumerary small marker chromosome. This marker chromosome was proved to be bisatellited and dicentric by G-, C-, R-banding and the silverstaining technique.     

Structural Characterization of the Ectodomain of a Disintegrin and Metalloproteinase-22 (ADAM22), a Neural Adhesion Receptor Instead of Metalloproteinase: INSIGHTS ON ADAM FUNCTION?

ADAMs (a disintegrin and metalloproteinases) are a family of multidomain transmembrane glycoproteins with diverse roles in physiology and diseases, with several members being drug targets for cancer and inflammation therapies. The spatial organization of the ADAM extracellular segment and its influence on the function of ADAMs have been unclear. Although most members of the ADAM family are active zinc metalloproteinases, 8 of 21 ADAMs lack functional metalloproteinase domains and are implicated in protein-protein interactions instead of membrane protein ectodomain shedding. One of such non-proteinase ADAMs, ADAM22, acts as a receptor on the surface of the postsynaptic neuron to regulate synaptic signal transmission. The crystal structure of the full ectodomain of mature human ADAM22 shows that it is a compact four-leaf clover with the metalloproteinase-like domain held in the concave face of a rigid module formed by the disintegrin, cysteine-rich, and epidermal growth factor-like domains. The loss of metalloproteinase activity is ensured by the absence of critical catalytic residues, the filling of the substrate groove, and the steric hindrance by the cysteine-rich domain. The structure, combined with calorimetric experiments, suggests distinct roles of three putative calcium ions bound to ADAM22, with one in the metalloproteinase-like domain being regulatory and two in the disintegrin domain being structural. The metalloproteinase-like domain contacts the rest of ADAM22 with discontinuous, hydrophilic, and poorly complemented interactions, suggesting the possibility of modular movement of ADAM22 and other ADAMs. The ADAM22 structure provides a framework for understanding how different ADAMs exert their adhesive function and shedding activities.The ADAM² family includes over 20 multidomain type I transmembrane glycoproteins that have diverse functions in cell adhesion/signaling and ectodomain shedding of cell-surface receptors or ligands (1, 2). They are broadly implicated in various physiological processes including sperm-egg interactions, development and function of the nervous system (e.g. cell-fate determination, axon guidance, and myelination), immune responses, and embryogenesis (2, 3). Dysregulation of the ADAM family is linked to a wide variety of pathological states including cancer, cardiovascular disease, asthma, Alzheimer disease, and inflammation (3–5). Several ADAMs have been pursued as therapeutic targets (6, 7).ADAMs, together with their phylogenic relatives, the P- III class snake venom metalloproteinases (SVMPs) and ADAMTSs (ADAM with thrombospondin type-1 motif), constitute a subgroup of the metzincin clan of zinc proteinases (8, 9). The extracellular segments of ADAMs contain a prodomain that gets cleaved off during secretion, a metalloproteinase-like domain, a disintegrin domain, and a cysteine-rich domain, which are shared by SVMPs and ADAMTSs, and a unique epidermal growth factor-like domain preceding the transmembrane segment. All ADAMs contain metalloproteinase-like domains, but in humans, only 13 of the 21 members in the family possess the complete zinc binding environment (the HEXGHXXGXXHD sequence motif and the Met turn) in the domain (10). Although these proteolytically active ADAMs can shed cell-surface proteins from the plasma membrane, the other ADAMs are suggested to be non-enzymatic cell adhesion molecules (11, 12). Several ADAMs have been reported to interact with integrins, and the disintegrin-like domains of ADAMs have been suggested for this interaction (13). Despite these suggestions, structural proof that the ADAMs without canonical zinc-binding motif lack enzymatic activities has been absent, and it remains unclear how these molecules are structurally configured to support protein-protein interaction instead of ectodomain shedding.ADAM22 (also named MDC2), one of such postulated non-catalytic ADAMs, was recently identified to serve as the postsynaptic receptor for the secreted neurotransmission modulator LGI-1 at neural synapses (14). The study supports that some ADAMs can function as adhesion molecules rather than metalloproteinases. ADAM22 is predominantly expressed in the nervous systems (15, 16). The Adam22^−/− mice suffered from hypomyelination of peripheral nerves, leading to ataxia, and died before weaning (17). At the synapse, LGI-1 and ADAM22 form a tertiary complex with postsynaptic density-95 (PSD-95), a major scaffolding protein localized to the postsynaptic density of brain synapses, which is associated with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor and other signaling proteins (14). In this complex, the extracellular domain of ADAM22 interacts with LGI-1, whereas its cytoplasmic PDZ-binding motif recruits PSD-95. The link of ADAM22 and LGI-1 to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor established their roles in glutamate neurotransmission, consistent with genetic data that all these molecules are associated with epilepsy (17–19). Recently, it was further demonstrated that LGI-1 and LGI-4 bind to ADAM22, ADAM23, and ADAM11 (20).Although ADAMs are functionally important as sheddases or adhesion receptors, the structural information about the ADAM family is limited to only isolated domains, such as the metalloproteinase domains of ADAM17 and ADAM33 and the incomplete disintegrin cysteine-rich domains of ADAM10 (21–23). Their relatives, SVMPs from the snake venom, including VAP-1, VAP-2, and RVV-X (24–26), have revealed a “C”-shaped molecular architecture. These SVMP structures and partial ADAM structures, along with those of the ADAMTS family proteins (27–29), shed light on the general mechanisms of substrate recognition and cleavage by the proteinase-type ADAMs. However, there is little structural information on those non-catalytic ADAMs, which serve as adhesion receptors. In addition, despite a low resolution electron microscopic (EM) analysis of the soluble form of pro-ADAM12, which suggested that the prodomain represents one of the leaves of the four-leaf clover-shaped ADAM12 (30), the structure of a complete ADAM ectodomain, being catalytic or non-catalytic, has been lacking. Here we report the crystal structure of the entire ectodomain of mature ADAM22.     

Why is PTPN22 a good candidate susceptibility gene for autoimmune disease?

The PTPN22 locus is one of the strongest risk factors outside of the major histocompatability complex that associates with autoimmune diseases. PTPN22 encodes lymphoid protein tyrosine phosphatase (Lyp) which is expressed exclusively in immune cells. A single base change in the coding region of this gene resulting in an arginine to tryptophan amino acid substitution within a polyproline binding motif associates with type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosis, Hashimotos thyroiditis, Graves disease, Addison's disease, Myasthenia Gravis, vitiligo, systemic sclerosis juvenile idiopathic arthritis and psoriatic arthritis. Here, we review the current understanding of the PTPN22 locus from a genetic, geographical, biochemical and functional perspective.     

白介素22

近两年 ,发现了多种白介素 10家族新成员 :黑素瘤分化相关基因 7产物 (ｍｅｌａｎｏｍａｄｉｆｆｅｒｅｎｔｉａｔｉｏｎ ａｓｓｏｃｉａｔｅｄｇｅｎｅ 7,ＭＤＡ 7)、单纯疱疹病毒转化的Ｔ淋巴细胞产生的ＡＫＫ 15 5蛋白、Ｚｃｙｔｏ 10、巨细胞病毒编码ＩＬ 10 (ｃｍｖＩＬ 10 )、白介素 19(ＩＬ 19)、ＩＬ 2 0和ＩＬ 2 2。本文重点简述ＩＬ 2 2及其受体的研究进展。ＩＬ 2 2也称为ＩＬ 10相关Ｔ细胞衍生的可诱导因子 (ＩＬ 10 ｒｅｌａｔｅｄＴｃｅｌｌ ｄｅｒｉｖｅｄｉｎｄｕｃｉｂｅｆａｃｔｏｒ,ＩＬ ＴＩＦ)。比利时Ｌｕｄｗｉｇ癌…     

Unusual oxidative transformations of a steroidal 16α,17α,22-triol

A number of unexpected reactions were observed during attempts to invert configuration at C16 in 16α,17α,22-triol 3a. The PDC oxidation of 3a produced the D-seco-aldehyde 4a. Analogous compound 4b was obtained by Swern oxidation of the 16α,17α-dihydroxy-22-O-TES-ether 3b in addition to the desired 16-ketone 7. The unprotected triol 3a yielded pentacyclic products 5 and 6 under similar conditions. The Mitsunobu reaction of the triol 3a afforded 16-ketone 8 with inverted configuration of the side chain. During heating of a solution of 3a in THF with NaH at reflux autoxidation to the 16-ketone cyclic hemiketal 5, identical to one of the Swern oxidation products, took place.     

22q11.2 Microduplication in a patient with 19p13.12–13.13 deletion

Background

The chromosome 22q11.2 region microduplication has been described in patients with variable phenotypes. Here we present a 3-month-old girl with both 22q11.2 microduplication and 19p13.12–13.13 deletion. The presence of both genomic imbalances in one patient has not been previously reported in literature.

Methods

A routine G-banding karyotype analysis was performed using peripheral lymphocytes. Chromosome microarray analysis (CMA) was done using Affymetrix CytoScan™ HD array.

Results

The result of karyotyping showed that the patient is 46,XX,t(12;19)(q24.3;p13.1), but CMA detected a 2.8 Mb microduplication within the region 22q11.2 (chr22: 18,648,866–21,465,659) and a 1.2 Mb deletion on the chromosome 19at band p13.12–p13.13 (chr19: 13,107,938–14,337,347) in her genome, while no abnormalities were identified on 12q24.3. The 3-month-old girl presented with microcephaly, cleft palate, low set and retroverted ears, and facial dysmorphism which consisted of the following: a long narrow face, widely spaced eyes, downslanting palpebral fissures, broad nasal base, short philtrum, thin upper lip, and micro/retrognathia. She also had a congenital right pulmonary artery sling and tracheal stenosis and suffered from significant hypotonia and partial bilateral mixed hearing loss.

Conclusions

We report a case of 22q11.2 duplication syndrome with 19p13.12–13.13 deletion. Synergistic effect from the two genomic imbalances is likely responsible for the complicated clinical features observed in this patient.     

VEGF: a modifier of the del22q11 (DiGeorge) syndrome?

Hemizygous deletion of chromosome 22q11 (del22q11) causes thymic, parathyroid, craniofacial and life-threatening cardiovascular birth defects in 1 in 4,000 infants. The del22q11 syndrome is likely caused by haploinsufficiency of TBX1, but its variable expressivity indicates the involvement of additional modifiers. Here, we report that absence of the Vegf164 isoform caused birth defects in mice, reminiscent of those found in del22q11 patients. The close correlation of birth and vascular defects indicated that vascular dysgenesis may pathogenetically contribute to the birth defects. Vegf interacted with Tbx1, as Tbx1 expression was reduced in Vegf164-deficient embryos and knocked-down vegf levels enhanced the pharyngeal arch artery defects induced by tbx1 knockdown in zebrafish. Moreover, initial evidence suggested that a VEGF promoter haplotype was associated with an increased risk for cardiovascular birth defects in del22q11 individuals. These genetic data in mouse, fish and human indicate that VEGF is a modifier of cardiovascular birth defects in the del22q11 syndrome.     

Purification and biochemical characterization of a detergent stable α-amylase from Pseudomonas stutzeri AS22

This study reports the purification and biochemical characterization of a novel maltotetraose-forming-α-amylase from Pseudomonas stutzeri AS22, designated PSA. The P. stutzeri α-amylase (PSA) was purified from the culture supernatant to homogeneity by Sepharose mono Q anion exchange chromatography, ultrafiltration and Sephadex G-100 gel filtration, with a 37.32-fold increase in specific activity, and 31% recovery. PSA showed a molecular weight of approximately 57 kDa by SDS-PAGE. The N-terminal amino acid sequence of the first 7 amino acids was DQAGKSP. This enzyme exhibited maximum activity at pH 8.0 and 55°C, performed stably over a broad range of pH 5.0 ≈ 12.0, but rapidly lost activity above 50°C. Both potato starch and Ca²⁺ ions have a protective effect on the thermal stability of PSA. The enzyme activity was inhibited by Hg²⁺, Mn²⁺, Cd²⁺, Cu²⁺, and Co²⁺, and enhanced by Ba²⁺. PSA belonged to the EDTA-sensitive α-amylase. The purified enzyme showed high stability towards surfactants (Tween 20, Tween 80 and Triton X-100), and oxidizing agents, such as sodium per borate and H₂O₂. In addition, PSA showed excellent compatibility with a wide range of commercial solid and liquid detergents at 30°C, suggesting potential application in the detergent industry. Maltotetraose was the specific end product obtained after hydrolysis of starch by the enzyme for an extended period of time, and was not further degraded.     

大豆花药优势表达基因GmFLA22a调控雄性育性的功能研究

我国大豆对外依赖度高,加速提高大豆产量是目前亟需解决的问题。利用杂种优势是大幅提高作物产量的有效途径之一,近年来基于隐性核不育基因开发的智能雄性不育系统,为快速利用大豆杂种优势提供了可能。但是,大豆雄性不育基因研究相对滞后。本研究基于课题组大豆花器官转录组数据,筛选到在大豆早期花药中优势表达基因GmFLA22a,编码含有FAS1结构域的成束状阿拉伯半乳糖蛋白,亚细胞定位表明其可能在内质网中发挥功能。利用基因编辑技术获得Gmfla22a突变体,突变体植株在营养生长阶段与对照组相比没有明显差异,但在生殖生长阶段表现为结实率显著降低。Gmfla22a突变体花粉活力和花粉萌发率均无明显异常,组织切片并染色观察发现,突变体植株花药室壁增厚,花粉粒释放延迟、不完全,这可能是导致Gmfla22a结实率降低的原因。综上,本研究初步揭示GmFLA22a可能参与调控大豆雄性育性,为深入揭示其分子功能提供重要遗传材料,同时为大豆杂种优势利用提供基因资源和理论依据。     

HSP22研究进展

HSP22是小热休克蛋白超家族成员之一,主要在脑、心肌和骨骼肌广泛表达,而在子宫、前列腺、肺和肾脏等组织表达一般.当各种物理、化学等因素刺激时,可启动HSP22 mRNA快速表达;再通过HSP22 N末端区域和(或)C末端区域特定位点的突变或磷酸化反应,不同构象间相互转化及作用,在保持伴侣活性、激酶活性、触发炎性介质释放、抗凋亡与致凋亡和保护细胞骨架等方面起主要作用.其活性下降会导致遗传性末梢运动神经病、Alzheimer病、结蛋白相关心肌病、乳腺癌及白内障等相关疾病的发生发展.由于其在生命领域的特殊功能作用,目前生物医学界对其研究广泛.本文收集近期国内外文献,从分子和细胞水平综述了HSP22在基因表达、分子结构、生物学活性及与临床疾病关系的最新研究进展,以供学习交流.     

3β-Acetoxyhopan-1β,22-diol,a triterpene from the lichen Pseudoparmelia texana

From the lichen Pseudoparmelia texana the triterpene 3β-acetoxyhopan-1β,22-diol has been isolated and its structure elucidated.     

Linkage of recessive Robinow syndrome to a 4 cM interval on chromosome 9q22

Autosomal recessive Robinow syndrome is a form of mesomelic dwarfism with multiple rib and vertebral anomalies. Using autozygosity mapping we have identified a genetic locus (RBNW1) for this syndrome at chromosome 9q22 in seven consanguineous families from Oman. Our results indicate that the gene lies within a 4 cM region between markers D9S1836 and D9S1803 (maximum multipoint LOD score 12.3). In addition, we have analysed two non-Omani families with autosomal recessive Robinow and found no genetic heterogeneity.     

小鼠腹水型肝癌H22a细胞浆内磷蛋白磷酸酶活力调节的研究

小鼠腹水型肝癌细胞胞浆内磷蛋白磷酸酶对磷酸化的组蛋白、酪蛋白、鱼精蛋白具有脱磷酸化活力,而对小分子底物P-Ser、P-Thr、P-Tyr、PNPP等无活力。二价金属离子Mn~(2+)、Co~(2+)、Mg~(2+)对酶有明显激活作用,而Zn~(2+)、F~-、Pi对酶有明显抑制作用。代谢中间物G-6-P、G-1-P、F-6-P、F-1.6-2P、ATP、ADP、GTP对酶有抑制作用,而磷酸化氨基酸和环核苷酸对酶活影响很小。还试验了碱性蛋白质和酸性蛋白质对酶活力的影响,肝素和组蛋白均对酶活力有抑制作用,当两者混和后,其抑制作用会相互抵消。     

A controversial tumor marker: is SM22 a proper biomarker for gastric cancer cells?

SM22, a dominant protein in smooth muscle cells (SMCs), has been widely reported to be abnormally expressed in many solid tumors. However, the expression patterns of SM22 are not consistent in all tumors, not even in the same ones. Whether SM22 should be considered a tumor biomarker is still debated in different laboratories. Herein, we have carried out a systematical investigation to validate SM22 expression in the primary tissues of gastric cancer (GC). Of eight cases, seven samples were found in the elevated expression of SM22 proteins through proteomic analysis. The observation was further verified by the approaches of Western blotting and quantitative RT-PCR. Surprisingly, the results achieved from tissue microarray in 126 GC cases appeared contrary to the proteomic conclusion, in which the highly expressed SM22 was mainly found in smooth muscle layers, blood vessels, and myofibroblasts. This suggested that the increased abundance of SM22 in the cancerous regions was not caused by the presence of the GC cells. Furthermore, the expression of SM22 was measured in different GC cell lines and SMCs with Western blotting and quantitative RT-PCR. The results revealed that SM22 expression in SMCs was dramatically higher than that of the GC cells, which indicates that SM22 is unlikely to be a proper biomarker for GC. Instead, it can be considered a potential indicator for the abnormal developments of smooth muscles, blood vessels, or myofibroblasts triggered by tumorigenesis.     

成纤维细胞生长因子22(FGF22)的研究进展

成纤维细胞生长因子22(fibroblast growth factor 22)是成纤维细胞生长因子家族(FGFs)的成员之一。研究发现,FGF22主要在大脑和皮肤中表达并且能够影响大脑发育和神经突触的形成。由于FGF22在难治性癫痫发生机制中所发挥的特殊作用,有可能作为研究癫痫疾病的新的切入点。此外FGF22与脊髓损伤修复、神经系统疾病、皮肤癌、抑郁等疾病有着重要的联系。特别是在神经突出的形成过程中FGF22起着调节因子的作用。尽管作为重组蛋白药物的开发其功能和机制仍有待进一步研究,但相信FGF22所具备的生物学特性具有非常广阔的研究领域和应用价值。     

小鼠腹水型肝癌H22a细胞浆内一种特异性酸性磷酸酶的研究

<正> 许多实验室都报道从一些组织中纯化出的能使蛋白质的酪氨酸残基脱磷酸化的磷蛋白磷酸酶也具有使PNPP(对硝基酚磷酸钠)脱磷酸基团的活力。我们曾对小鼠腹水型H22a肝癌细胞胞浆中的磷蛋白磷酸酶进行了纯化和性质研究,在粗酶液经DEAE-Sephadex A50柱层析时,发现磷蛋白磷酸酶和对PNPP具酶活力的蛋白成分是可以分开的,本文对具PNPP酶活     

小鼠腹水型肝癌H22a细胞浆胞内磷蛋白磷酸酶的纯化和性质

 磷蛋白磷酸酶是磷酸化/脱磷酸化作用中重要的调节酶。本文建立了小鼠腹水型肝癌细胞胞浆内磷蛋白磷酸酶(PrP)的纯化方法。用~(32)P-酪蛋白为底物测定活力。经纯化的酶纯度提高1380倍,聚丙烯酰胺梯度凝胶电泳检查,只有一条泳带。用凝胶过滤法和聚丙烯酰胺梯度凝胶电泳法测得该酶分子量为200,000。该酶催化~(32)P-酪蛋白脱磷酸化反应的最适pH7.2,对热不稳定。