Lipoma Preferred Partner Gene Research Articles

LPP polymorphisms are risk factors for allergic rhinitis in the Chinese Han population.

Lipoma preferred partner (LPP) polymorphisms are related to immune diseases, but the role of LPP gene in the pathogenesis of allergic rhinitis (AR) is unclear. The current study aimed to explore the contribution of LPP variants to AR susceptibility in the Chinese Han population. A total of 992 healthy controls and 992 patients with AR were recruited. Agena MassARRAY system was applied for genotyping. Odds ratios (OR) and 95% confidence intervals (CI) adjusted by age, sex, and body mass index (BMI) were calculated to conduct the risk assessment of LPP variants in people with a predisposition to AR. Additionally, multifactor dimensionality reduction (MDR) was applied to identify high-order interaction models for AR risk. We found that rs2030519-G (p=0.027, OR: 1.15, 95% CI: 1.02-1.31), rs6780858-G (p=0.019, OR: 1.16, 95% CI: 1.03-1.32), and rs60946162-T (p=0.014, OR: 1.18, 95% CI: 1.03-1.34) were associated with increased susceptibility to AR. Subgroup analyses indicated the interaction of LPP polymorphisms in terms of age, gender, and BMI with AR susceptibility (p<0.05, OR>1). MDR analysis revealed that rs60946162 had the information gain (0.40%) of individual attribute regarding AR. Our results first determined that rs2030519, rs6780858, and rs60946162 were correlated with increased susceptibility to AR in the Chinese Han population, which add to our understanding of the impact of LPP gene variants on AR development.

Disparate Mutations in B-Acute Lymphoblastic Leukemia Among African American and European American Children

Background: B-acute lymphoblastic leukemia (B-ALL) is considered to be the most common malignancy diagnosed in childhood and leading cause of cancer-related death in children. There have been advances in the efficacy of multi-agent chemotherapy and stratification of treatment intensity according to clinical features of the patient, biologic features of leukemia cells, and early response to treatment. These advances herald the promise and challenges of precision medicine strategies that integrate leukemia genomics into contemporary therapy. Despite this progress, there are unmet needs related to the treatment of B-ALL. Among them the incidence varies according to race: African American (AA) children have significantly lower incidence of B-ALL compared to European American (EA). However, studies have shown that AA children have significantly lower survival rates compared to EA children. This disparity is not related to socioeconomic variables, suggesting a molecular basis for the lower survival rates of AA. Here we present a study showing race-specific genetic aberrations involved in leukemogenesis that may contribute to health disparities in B-ALL in AA and EA children.Aims: In a population of AA and EA pediatric B-ALL patients: 1) Discover the genomic susceptibility architecture at validated loci and determine whether genetic variants confer population-specific risks. 2) Define the landscape of molecular perturbation and genomic alterations. 3) Identify aberrant canonical pathways in leukemogenesis.Methods: A total of 20 newly diagnosed pediatric patients were utilized in our study (5 AA and 15 EA). Ages ranged between 1 and 18 years. Clinical history, hemogram, flow cytometry, immunophenotypic, morphologic, cytogenetic and prior molecular data were reviewed. None of the patients in our study had a relapse. Median percent cellularity present in the bone marrow aspirates was 100% (70% - 100%). Median percent of blasts was 94.8% (64.5% - 99.0%). Following manufacturer protocol (Qiagen, QIAmp DNA blood kit), 200µl of frozen bone marrow aspirates were used to extract the DNA. Following quality control on a Qubit fluorometer and RNA bioanalyzer, the samples were submitted to a translational genomics core for library preparation and whole-exome sequencing (TruSeq Exome, Illumina). Bioinformatics analysis was performed and genetic variants for each sample were identified.Results: We identified specific germ-line mutations within the most widely accepted cancer-related genes related to B-ALL. Most genetic aberrations (339) were shared between AA and EA, for example those present in the Anaplastic Lymphoma Receptor Tyrosine Kinase (ALK) gene. Some genes with genetic aberrations were specific of AA (58) such as, Lipoma Preferred Partner Gene (LPP) and others specific for EA (52) such as, Leukemia Inhibitory Factor Receptor (LIFR). The ingenuity pathway analysis revealed these genes clustered in race-specific canonical pathways. In AA, the specific pathways were related to telomerase signaling and cancer signaling. In EA, the specific pathways were related to stem cell pluripotency and hereditary cancers. Our findings suggest the value of whole exome sequencing as a tool for development of individual gene signatures and gene scores for AA and EA children afflicted by B-ALL.Conclusions: Overall, the prevalence of genetic aberrations in B-ALL may contribute to differences in incidences and outcomes between AA and EA children. Aberrant biological networks revealed by our study, provide information on distinguishing genetic aberrations and signaling networks that may be involved in race-specific leukemogenesis. Furthermore, our findings suggest that it may be possible to develop a whole-exome sequencing gene signature in B-ALL to help define a race-specific prognostic assay for B-ALL in bone marrow aspirates. In the future, the biomarker panel derived from this study will help guide risk stratification and treatments based on race and advance the prognosis of B-ALL in AA children. These findings may ultimately impact targeted disease management and contribute to the elimination of the disparate outcomes in B-ALL among AA children.Funding: Hyundai Hope on Wheels Scholar Grant, UMMC Division of Pediatric Hematology Oncology [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

3′UTR SNPs in the LPP gene associated with Immunoglobulin A nephropathy risk in the Chinese Han population

The purpose of this study was to investigate the relationship between Lipoma preferred partner (LPP) gene polymorphisms and the risk of Immunoglobulin A nephropathy (IgAN) in the Chinese Han population. In this case-control study, we genotyped three single nucleotide polymorphisms (SNPs) of the LPP gene in 357 IgAN cases and 384 controls, using Agena Bioscience MassARRAY technology and assessed their association with IgAN using the χ2 test and genetic model analysis. The odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess risk and were adjusted for age and gender by logistic regression. In the allele model, there were significant associations between LPP rs1064607 (OR = 1.24; 95% CI = 1.01–1.53; p = 0.041), rs3796283 (OR = 1.32; 95% CI = 1.08–1.63; p = 0.008), and rs2378456 (OR = 1.29; 95% CI = 1.05–1.59; p = 0.016), as well as an increased risk of IgAN. In the dominant model, the “G/C-C/C” genotypes of rs1064607 (p = 0.023), the “G/A-G/G” genotypes of rs3796283 (p = 0.0013) and the “G/C-C/C” genotypes of rs2378456 (p = 0.00052) were risk factors for IgAN. The results of the stratified analysis showed that rs3796283 and rs2378456 were connected with susceptibility to IgAN in different subgroups. Our data may provide new evidence to research the etiology of IgAN.

Race-specific genetic aberrations in B-acute lymphoblastic leukemia in children.

e22000 Background: B-Acute Lymphoblastic Leukemia (B-ALL) is the most common childhood cancer and the leading cause of death in children. Studies have shown that African-American (AA) children have significantly lower survival rates compared to European-American (EA) children. This disparity is not related to socioeconomic variables, suggesting a molecular basis for the lower survival. Here we present a study showing genetic aberrations (GA) involved in race-specific leukemogenesis and contribute to health disparities in B-ALL in AA and EA children. Methods: A total of 20 newly diagnosed pediatric patients were studied (5 AA and 15 EA) at University of Mississippi Medical Center. Ages range between 1 and 18 years with a median age of 4 years. None of the patients in our study had a relapse. Frozen bone marrow (BM) aspirates were used to extract DNA and whole-exome DNA sequencing was performed, focusing on race and B-ALL specific germ-line mutations. Results: Most GA were shared between AA and EA, for example those present in the Anaplastic Lymphoma Receptor Tyrosine Kinase (ALK) gene. Some genes with GA were specific to AA and others to EA. Genetic non-synonymous germ-line aberrations were identified such as, Lipoma Preferred Partner Gene, in AA and Leukemia Inhibitory Factor Receptor, in EA. Ingenuity pathway analysis revealed these genes clustered in race-specific canonical pathways. In AA, the pathways were related to telomerase signaling and cancer signaling. While in EA, it was related to stem cell pluripotency and hereditary cancer. Conclusions: The prevalence of GA in B-ALL may contribute to differences in outcomes between AA and EA children. Aberrant biological networks revealed by our study, will provide information on distinguishing signaling networks involved in race-specific leukemogenesis. Our study provides a strong basis to develop a race-specific prognostic assay for B-ALL in BM aspirates. In the future, this can help guide risk stratification and treatments based on race and advance the prognostication of B-ALL in AA children. Funding: Hyundai Hope on Wheels Scholar Grant, UMMC Division of Pediatric Hematology Oncology.

Bariatric Endocrinology, Adiposopathy, and Disorders of Regional Fat Distribution

Bariatric Endocrinology, Adiposopathy, and Disorders of Regional Fat Distribution

Lasp1gene disruption is linked to enhanced cell migration and tumor formation

Lasp1 is an actin-binding, signaling pathway-regulated phosphoprotein that is overexpressed in several cancers. siRNA knockdown in cell lines retards cell migration, suggesting the possibility that Lasp1 upregulation influences cancer metastasis. Herein, we utilized a recently developed gene knockout model to assess the role of Lasp1 in modulating nontransformed cell functions. Wound healing and tumor initiation progressed more rapidly in Lasp1(-/-) mice compared with Lasp1(+/+) controls. Embryonic fibroblasts (MEFs) derived from Lasp1(-/-) mice also migrated more rapidly in vitro. These MEFs characteristically possessed increased focal adhesion numbers and displayed more rapid attachment compared with wild-type MEFs. Differential microarray analyses revealed alterations in message expression for proteins implicated in cell migration, adhesion, and cytoskeletal organization. Notably, the focal adhesion protein, lipoma preferred partner (LPP), a zyxin family member and putative Lasp1 binding protein, was increased about twofold. Because LPP gene disruption reduces cell migration, we hypothesize that LPP plays a role in enhancing the migratory capacity of Lasp1(-/-) MEFs, perhaps by modifying the subcellular localization of other motility-associated proteins. The striking contrast in the functional effects of loss of Lasp1 in innate cells compared with cell lines reveals distinct differences in mechanisms of motility and attachment in these models.

Targeted disruption of the mouse Lipoma Preferred Partner gene

LPP (Lipoma Preferred Partner) is a zyxin-related cell adhesion protein that is involved in the regulation of cell migration. We generated mice with a targeted disruption of the Lpp gene and analysed the importance of Lpp for embryonic development and adult functions. Aberrant Mendelian inheritance in heterozygous crosses suggested partial embryonic lethality of Lpp−/− females. Fertility of Lpp−/− males was proven to be normal, however, females from Lpp−/−×Lpp−/− crosses produced a strongly reduced number of offspring, probably due to a combination of female embryonic lethality and aberrant pregnancies. Apart from these developmental and reproductive abnormalities, Lpp−/− mice that were born reached adulthood without displaying any additional macroscopic defects. On the other hand, Lpp−/− mouse embryonic fibroblasts exhibited reduced migration capacity, reduced viability, and reduced expression of some Lpp interaction partners. Finally, we discovered a short nuclear form of Lpp, expressed mainly in testis via an alternative promoter.

Smooth Muscle Expression of Lipoma Preferred Partner Is Mediated by an Alternative Intronic Promoter That Is Regulated by Serum Response Factor/Myocardin

Lipoma preferred partner (LPP) was recently recognized as a smooth muscle marker that plays a role in smooth muscle cell migration. In this report, we focus on the transcriptional regulation of the LPP gene. In particular, we investigate whether LPP is directly regulated by serum response factor (SRF). We show that the LPP gene contains 3 evolutionarily conserved CArG boxes and that 1 of these is part of an alternative promoter in intron 2. Quantitative RT-PCR shows that this alternative promoter directs transcription specifically to smooth muscle containing tissues in vivo. By using chromatin immunoprecipitation, we demonstrate that 2 of the CArG boxes, including the promoter-associated CArG box, bind to endogenous SRF in cultured aortic smooth muscle cells. Electrophoretic mobility-shift assays show that the conserved CArG boxes bind SRF in vitro. In reporter experiments, we show that the alternative promoter has transcriptional capacity that is dependent on SRF/myocardin and that the promoter associated CArG box is required for that activity. Finally, we show by quantitative RT-PCR that the alternative promoter is strongly downregulated in SRF-deficient embryonic stem cells and in smooth muscle tissues derived from conditional SRF knockout mice. Collectively, our data demonstrate that expression of LPP in smooth muscle is mediated by an alternative promoter that is regulated by SRF/myocardin.

Chromosomal Translocations Fusing theBCL6Gene to Different Partner Loci Are Recurrent in Primary Central Nervous System Lymphoma and May Be Associated With Aberrant Somatic Hypermutation or Defective Class Switch Recombination

Primary central nervous system lymphomas (PCNSLs) are diffuse large B cell lymphomas confined to the brain. Only minimal data exist on chromosomal aberrations underlying PCNSLs. We studied 41 PCNSLs by fluorescence in situ hybridization for breakpoints affecting the BCL6 locus in chromosomal band 3q27. Of 37 cases evaluable, 14 (38%) carried a breakpoint in the BCL6 locus. Two of these showed juxtaposition of BCL6 to the IGH locus. In 4 cases, the BCL6 breakpoints were cloned using long-distance inverse polymerase chain reaction. All breakpoints were located within the BCL6 major translocation cluster. The translocation partners were the IGH gene in 14q32.33, the IGL gene in 22q11.22, and the histone 1 H4I gene in 6p22.1. In the fourth case, a deletion in 3q leads to loss of an 837-kb fragment extending from the first intron of BCL6 to the third intron of the lipoma-preferred partner (LPP) gene. This deletion may bring the BCL6 gene under the control of regulatory elements of the LPP gene or the miRNA-28 gene located in intron 4 of LPP. DNA sequence analysis of the junctional sequences provided evidence that aberrant class switch recombination or somatic hypermutation may be involved in the generation of BCL6 translocations.

ZRP-1, a Zyxin-related Protein, Interacts with the Second PDZ Domain of the Cytosolic Protein Tyrosine Phosphatase hPTP1E

Protein-protein interactions play an important role in the specificity of cellular signaling cascades. By using the yeast two-hybrid system, a specific interaction was identified between the second PDZ domain of the cytosolic protein tyrosine phosphatase hPTP1E and a novel protein, which was termed ZRP-1 to indicate its sequence similarity to the Zyxin protein family. The mRNA encoding this protein is distributed widely in human tissues and contains an open reading frame of 1428 base pairs, predicting a polypeptide of 476 amino acid residues. The deduced protein displays a proline-rich amino-terminal region and three double zinc finger LIM domains at its carboxyl terminus. The specific interaction of this novel protein with the second PDZ domain of hPTP1E was demonstrated both in vitro, using bacterially expressed proteins, and in vivo, by co-immunoprecipitation studies. Deletion analysis indicated that an intact carboxyl terminus is required for its interaction with the second PDZ domain of hPTP1E in the yeast two-hybrid system and suggested that other sequences, including the LIM domains, also participate in the interaction. The genomic organization of the ZRP-1 coding sequence is identical to that of the lipoma preferred partner gene, another Zyxin-related protein, suggesting that the two genes have evolved from a recent gene duplication event.

Truncated and chimeric HMGI-C genes induce neoplastic transformation of NIH3T3 murine fibroblasts.

Overexpression of the high mobility group I (HMGI) proteins is often associated with the malignant phenotype. Moreover, many benign human tumors, mainly of mesenchymal origin, are characterized by rearrangements of the HMGI-C gene. In most cases, HMGI-C alterations involve breaks within the third intron of the gene resulting in aberrant transcripts carrying exons from 1-3, which encode the three DNA binding domains, fused to ectopic sequences. Here, we show that the expression of a truncated form of HMGI-C protein carrying only the three DNA-binding domains, or of a fusion protein carrying the three DNA-binding domains of HMGI-C and the LIM domains of the lipoma preferred partner gene (LPP) protein, causes malignant transformation of NIH3T3 cells. The unrearranged wild-type HMGI-C cDNA did not exert any transforming activity. These findings indicate that rearranged forms of HMGI-C play a role in cell transformation.

LPP,the Preferred Fusion Partner Gene ofHMGICin Lipomas, Is a Novel Member of the LIM Protein Gene Family

A major cytogenetic subgroup of lipomas is characterized by recurrent chromosome aberrations, mainly translocations, that involve chromosome segment 12q13–q15. Multiple chromosomes have been found as the translocation partners of chromosome 12 but 3q27–q28 is preferentially involved. In previous studies, it has been shown that the high mobility group (HMG) protein geneHMGICat 12q15 is consistently rearranged as a consequence of these translocations. Here, we report the identification and characterization of the chromosome 3-derived translocation partner gene, which we have designatedLPP(lipoma preferred partner gene). Using 3′-RACE analysis ofHMGICfusion transcripts in lipoma cell line Li-501/SV40, ectopic genetic sequences were obtained, which by CASH (chromosome assignment using somatic cell hybrids) and FISH (fluorescencein situhybridization) analysis were found to originate from chromosome segment 3q27–q28. In Northern blot analysis, an mRNA of over 10 kb was detected by these ectopic sequences in a variety of human tissues but not in brain and peripheral blood leukocytes. Upon partial cDNA cloning, features of the genetic organization ofLPPwere established. The gene was found to span a genomic region of over 400 kb. Nucleotide sequence analysis of a composite cDNA ofLPPrevealed an open reading frame of 1836 nucleotides encoding a proline-rich protein containing a leucine-zipper motif in its amino-terminal region and three LIM domains in its carboxy-terminal region. TheLPP-encoded protein should be classified as a novel member of the group 3 proteins of the LIM protein gene family. Using reverse transcriptase combined with polymerase chain reactions in the analysis of a number of lipoma cell lines and primary lipomas, it appeared thatLPPis frequently rearranged also in cases without a cytogenetically detectable involvement of 3q27–q28. Two alternativeHMGIC/LPPhybrid transcripts have been detected; the difference between them is mainly the presence of either two or three LIM domains in the predicted HMGI-C/LPP fusion proteins.