Trisomy 22.

The existence of a trisomy 22 has been definitely established by newer methods of karyotype analysis which permit distinction between the acrocentric chromosomes of group G. Trisomy 22 is much rarer than trisomy 21. This report presents presumptive evidence that the cat eye syndrome (CES), the so-called "trisomy 22" (T22), the intermediate cases (IM) with cardinal symptoms of CES and T22, and some cases of mental retardation with rather unspecific symptoms are variants of the same disease entity. For T22, CES and one abortive case the extra chromosome was clearly identified as number 22 chromosome with or without partial deletion of the long arm. An interesting and presently not fully understood feature of trisomy 22 is its frequent familial incidence.     

A map of 22 loci on human chromosome 22.

We constructed a genetic linkage map of the entire long arm of human chromosome 22 with 30 polymorphic markers, defining 22 loci. The map consists of a continuous linkage group 110 cM long, when male and female recombination fractions are combined; average distance between the loci is 5.2 cM. All loci were placed on the map with high support against alternative orders (odds in excess of 1000:1). The order of loci presented in our map is in full agreement with that of the previous linkage maps of chromosome 22 and with the physical assignment of markers. Two markers included in this map, KI-831 (D22S212) and pEFZ31 (D22S32), allowed us to better define the region of the (11;22) translocation breakpoint specific for Ewing sarcoma. Ten additional polymorphic markers were placed on the 22-loci map with odds lower than 1000:1 against alternative locations. In total, we have introduced 29 new markers on the linkage map of chromosome 22.     

Crystal structure of the IL-22/IL-22R1 complex and its implications for the IL-22 signaling mechanism

Interleukin-22 (IL-22) is a member of the interleukin-10 cytokine family, which is involved in anti-microbial defenses, tissue damage protection and repair, and acute phase responses. Its signaling mechanism involves the sequential binding of IL-22 to interleukin-22 receptor 1 (IL-22R1), and of this dimer to interleukin-10 receptor 2 (IL-10R2) extracellular domain. We report a 1.9A crystal structure of the IL-22/IL-22R1 complex, revealing crucial interacting residues at the IL-22/IL-22R1 interface. Functional importance of key residues was confirmed by site-directed mutagenesis and functional studies. Based on the X-ray structure of the binary complex, we discuss a molecular basis of the IL-22/IL-22R1 recognition by IL-10R2. STRUCTURED SUMMARY:     

An increased proportion of circulating Th22 and Tc22 cells in psoriasis

Psoriasis is a common dermatosis mediated by T cells. This study investigated the correlation of Th22 cells and Tc22 cells with psoriasis. A total of 30 psoriasis patients and 11 age- and sex-matched healthy controls were recruited for this study. The proportions of circulating Th22 and Tc22 cells, expression of aryl hydrocarbon receptor, and IL-22 levels in the psoriasis patients were significantly higher than those in the control subjects (p < 0.05). There was a positive correlation between the proportion of circulating Th22 cells, IL-22 levels, and PASI score. The IL-22 levels and PASI score were also positively correlated. There was no correlation between the proportion of circulating Tc22 cells and IL-22 level or PASI score. These data are consistent with Th22 cells involvement in the pathogenesis of psoriasis.     

Crystal structure of a soluble decoy receptor IL-22BP bound to interleukin-22

Interleukin-22 (IL-22) plays an important role in the regulation of immune and inflammatory responses in mammals. The IL-22 binding protein (IL-22BP), a soluble receptor that specifically binds IL-22, prevents the IL-22/interleukin-22 receptor 1 (IL-22R1)/interleukin-10 receptor 2 (IL-10R2) complex assembly and blocks IL-22 biological activity. Here we present the crystal structure of the IL-22/IL-22BP complex at 2.75 Å resolution. The structure reveals IL-22BP residues critical for IL-22 binding, which were confirmed by site-directed mutagenesis and functional studies. Comparison of IL-22/IL-22BP and IL-22/IL-22R1 crystal structures shows that both receptors display an overlapping IL-22 binding surface, which is consistent with the inhibitory role played by IL-22 binding protein.

Structured summary

MINT-7010533: IL-22 BP (uniprotkb:Q969J5) and IL-22 (uniprotkb:Q9GZX6) bind (MI:0407) by X-ray crystallography (MI:0114)     

Structure of IL-22 bound to its high-affinity IL-22R1 chain

IL-22 is an IL-10 family cytokine that initiates innate immune responses against bacterial pathogens and contributes to immune disease. IL-22 biological activity is initiated by binding to a cell-surface complex composed of IL-22R1 and IL-10R2 receptor chains and further regulated by interactions with a soluble binding protein, IL-22BP, which shares sequence similarity with an extracellular region of IL-22R1 (sIL-22R1). IL-22R1 also pairs with the IL-20R2 chain to induce IL-20 and IL-24 signaling. To define the molecular basis of these diverse interactions, we have determined the structure of the IL-22/sIL-22R1 complex. The structure, combined with homology modeling and surface plasmon resonance studies, defines the molecular basis for the distinct affinities and specificities of IL-22 and IL-10 receptor chains that regulate cellular targeting and signal transduction to elicit effective immune responses.     

IL22/IL-22R Pathway Induces Cell Survival in Human Glioblastoma Cells

Interleukin-22 (IL-22) is a member of the IL-10 cytokine family that binds to a heterodimeric receptor consisting of IL-22 receptor 1 (IL-22R1) and IL-10R2. IL-22R expression was initially characterized on epithelial cells, and plays an essential role in a number of inflammatory diseases. Recently, a functional receptor was detected on cancer cells such as hepatocarcinoma and lung carcinoma, but its presence was not reported in glioblastoma (GBM). Two GBM cell lines and 10 primary cell lines established from patients undergoing surgery for malignant GBM were used to investigate the expression of IL-22 and IL-22R by using quantitative RT-PCR, western blotting and confocal microscopy studies. The role of IL-22 in proliferation and survival of GBM cell lines was investigated in vitro by BrdU and ELISA cell death assays. We report herein that the two subunits of the IL-22R complex are expressed on human GBM cells. Their activation, depending on exogenous IL-22, induced antiapoptotic effect and cell proliferation. IL-22 treatment of GBM cells resulted in increased levels of phosphorylated Akt, STAT3 signaling protein and its downstream antiapoptotic protein Bcl-xL and decreased level of phosphorylated ERK1/2. In addition, IL-22R subunits were expressed in all the 10 tested primary cell lines established from GBM tumors. Our results showed that IL-22R is expressed on GBM established and primary cell lines. Depending on STAT3, ERK1/2 and PI3K/Akt pathways, IL-22 induced GBM cell survival. These data are consistent with a potential role of IL-22R in tumorigenesis of GBM. Since endogenous IL-22 was not detected in all studied GBM cells, we hypothesize that IL-22R could be activated by immune microenvironmental IL-22 producing cells.     

Recurrent abortion associated with a balanced 22;22 translocation,or isochromosome 22q in a monozygous twin

Summary A 45,XX,t(22;22)(p11;q11) or 45,XX,i(22q) chromosomal rearrangement was found in a woman with a history of recurrent abortion. A twin sister did not have the translocation even though marker studies indicate that the twins are probably monozygotic.     

Interaction between fortilin and transforming growth factor-beta stimulated clone-22 (TSC-22) prevents apoptosis via the destabilization of TSC-22

Yeast two-hybrid screening was conducted using a human ovary cDNA library to search for a novel binding protein using transforming growth factor-beta stimulated clone-22 (TSC-22). The selected protein was fortilin, which has been characterized as a nuclear anti-apoptotic protein. Overexpression of fortilin in ovarian carcinoma cells reversed TSC-22-mediated apoptosis, and the inhibition of fortilin expression via small interfering RNA (siRNA) resulted in an increase in the apoptosis of ovarian carcinoma cells. Moreover, fortilin overexpression promoted the degradation of TSC-22. Thus, an interaction between fortilin and TSC-22 prevents apoptosis via the destabilization of TSC-22 in ovarian carcinoma cells.     

Competitive inhibition of cytochrome P-450scc by (22R)- and (22S)-22-aminocholesterol. Side-chain stereochemical requirements for C-22 amine coordination to the active-site heme

Two diastereomeric aminocholesterols, (22R)-22-aminocholesterol and (22S)-22-aminocholesterol, are both found to be potent inhibitors of the biosynthesis of pregnenolone from cholesterol by purified bovine mitochondrial P-450scc. Both steroids are competitive versus cholesterol, but the stereochemically correct analog (22R)-22-aminocholesterol is bound approximately 1000 times more tightly than (22S)-22-aminocholesterol. The dissociation constants are 25 nM and 13 microM, respectively. Direct comparisons between spectroscopic and enzymatic properties of the two enzymesterol complexes and the 22-amino-23,24-bisnor-5-cholen-3 beta-ol complex are made, underlining the importance of the stereochemistry at the C-22 position.     

The role of the IL-22/IL-22R1 axis in cancer

Interleukin-22 (IL-22) is an IL-10 family cytokine produced by T cells and innate lymphoid cells. The IL-22 signaling pathway orchestrates mucosal immune defense and tissue regeneration through pleiotropic effects including pro-survival signaling, cell migration, dysplasia and angiogenesis. While these functions can prevent initial establishment of tumors, they can also be hijacked by aggressive cancers to enhance tumor growth and metastasis. Thus, the role of the IL-22/IL-22R1 axis in cancer is complex and context-specific. Evidence of IL-22 involvement manifests as dysregulation of IL-22 expression and signaling in patients with many common cancers including those of the gut, skin, lung and liver. Unlike other cancer-associated cytokines, IL-22 has restricted tissue specificity as its unique receptor IL-22R1 is exclusively expressed on epithelial and tissue cells, but not immune cells. This makes it an attractive target for therapy as there is potential achieve anti-tumor immunity with fewer side effects. This review summarizes current findings on functions of IL-22 in association with general mechanisms for tumorigenesis as well as specific contributions to particular cancers, and ponders how best to approach further research in the field.     

A case of trisomy 22 with a probable Robertsonian translocation 21/22

Summary A 2-year-old girl with a probable trisomy-22 translocation is described. The principal clinical symptoms described by the authors who have reported cases with proved trisomy 22 are presented. A probable 46, XX,-21,+t(21q;22q) karyotype was established in the patient. The proband's clinical picture is compared with other trisomy 22 cases described in the literature. The incidence of this trisomy among the human population is discussed.     

A 22/22 translocation carrier with recurrent abortions demonstrated by a Giemsa banding technique

Summary a 22/22 Robertsonian translocation has been identified in a woman with recurrent abortions by a Giemsa banding technique. Cytogenetic studies of the embryonic tissue derived from one of her spontaneous abortions have demonstrated that the aborted fetus had a 46,XX,-22,+t(22q22q) karyotype.     

A novel haem-binding interface in the 22 kDa haem-binding protein p22HBP

The 22 kDa haem-binding protein, p22HBP, is highly expressed in erythropoietic tissues and binds to a range of metallo- and non-metalloporphyrin molecules with similar affinities, suggesting a role in haem regulation or synthesis. We have determined the three-dimensional solution structure of p22HBP and mapped the porphyrin-binding site, which comprises a number of loops and a alpha-helix all located on a single face of the molecule. The structure of p22HBP is related to the bacterial multi-drug resistance protein BmrR, and is the first protein with this fold to be identified in eukaryotes. Strikingly, the porphyrin-binding site in p22HBP is located in a similar position to the drug-binding site of BmrR. These similarities suggest that the broad ligand specificity observed for both BmrR and p22HBP may result from a conserved ligand interaction mechanism. Taken together, these data suggest that the both the fold and its associated function, that of binding to a broad range of small hydrophobic molecules, are ancient, and have been adapted throughout evolution for a variety of purposes.     

Incomplete trisomy 22

Summary Two brothers with duplication of the distal segment of 22q inherited from a t(6;22)(q27;13) translocation carrier mother presented with intraurine growth retardation, congenital hydrocephalus, cleft palate, genital hypoplasia with cryptorchidism and hypospadias, and similar facial features including mongoloid position of eyeaxes, hypertelorism, small nose with prominent bridge, prominent upper lip, and small mandible. In addition the second sib revealed renal hypoplasia, arrhinencephaly and pentalogy of Fallot. The patients died at ages eight days and one day, respectively. The two brothers appear to be the first instances of familial trisomy 22q13qter.     

Interleukin-22 forms dimers that are recognized by two interleukin-22R1 receptor chains

Interleukin-22 (IL-22) is a class 2 cytokine whose primary structure is similar to that of interleukin 10 (IL-10) and interferon-γ (IFN-γ). IL-22 induction during acute phase immune response indicates its involvement in mechanisms of inflammation. Structurally different from IL-10 and a number of other members of IL-10 family, which form intertwined inseparable V-shaped dimers of two identical polypeptide chains, a single polypeptide chain of IL-22 folds on itself in a relatively globular structure. Here we present evidence, based on native gel electrophoresis, glutaraldehyde cross-linking, dynamic light scattering, and small angle x-ray scattering experiments, that human IL-22 forms dimers and tetramers in solution under protein concentrations assessable by these experiments. Unexpectedly, low-resolution molecular shape of IL-22 dimers is strikingly similar to that of IL-10 and other intertwined cytokine dimeric forms. Furthermore, we determine an ab initio molecular shape of the IL-22/IL-22R1 complex which reveals the V-shaped IL-22 dimer interacting with two cognate IL-22R1 molecules. Based on this collective evidence, we argue that dimerization might be a common mechanism of all class 2 cytokines for the molecular recognition with their respective membrane receptor. We also speculate that the IL-22 tetramer formation could represent a way to store the cytokine in nonactive form at high concentrations that could be readily converted into functionally active monomers and dimers upon interaction with the cognate cellular receptors.     

Echovirus 22 is an atypical enterovirus

Although echovirus 22 (EV22) is classified as an enterovirus in the family Picornaviridae, it is atypical of the enterovirus paradigm, typified by the polioviruses and the coxsackie B viruses. cDNA reverse transcribed from coxsackievirus B3 (CVB3) RNA does not hybridize to genomic RNA of EV22, and conversely, cDNA made to EV22 does not hybridize to CVB3 genomic RNA or to molecular clones of CVB3 or poliovirus type 1. EV22 cDNA does not hybridize to viral RNA of encephalomyocarditis virus or to a molecular clone of Theiler's murine encephalomyelitis virus, members of the cardiovirus genus. The genomic RNA of EV22 cannot be detected by the polymerase chain reaction using generic enteroviral primers. EV22 does not shut off host cell protein synthesis, and the RNA of EV22 is efficiently translated in vitro in rabbit reticulocyte lysates. Murine enterovirus-immune T cells recognize and proliferate against EV22 as an antigen in vitro, demonstrating that EV22 shares an epitope(s) common to enteroviruses but not found among other picornaviruses.