Gene Summary

Gene:RBP3; retinol binding protein 3
Aliases: IRBP, RBPI, RP66, D10S64, D10S65, D10S66
Summary:Interphotoreceptor retinol-binding protein is a large glycoprotein known to bind retinoids and found primarily in the interphotoreceptor matrix of the retina between the retinal pigment epithelium and the photoreceptor cells. It is thought to transport retinoids between the retinal pigment epithelium and the photoreceptors, a critical role in the visual process.The human IRBP gene is approximately 9.5 kbp in length and consists of four exons separated by three introns. The introns are 1.6-1.9 kbp long. The gene is transcribed by photoreceptor and retinoblastoma cells into an approximately 4.3-kilobase mRNA that is translated and processed into a glycosylated protein of 135,000 Da. The amino acid sequence of human IRBP can be divided into four contiguous homology domains with 33-38% identity, suggesting a series of gene duplication events. In the gene, the boundaries of these domains are not defined by exon-intron junctions, as might have been expected. The first three homology domains and part of the fourth are all encoded by the first large exon, which is 3,180 base pairs long. The remainder of the fourth domain is encoded in the last three exons, which are 191, 143, and approximately 740 base pairs long, respectively. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:retinol-binding protein 3
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: RBP3 (cancer-related)

Naru J, Aggarwal R, Mohanty AK, et al.
Identification of differentially expressed proteins in retinoblastoma tumors using mass spectrometry-based comparative proteomic approach.
J Proteomics. 2017; 159:77-91 [PubMed] Related Publications
In India, retinoblastoma is among the top five childhood cancers. Children mostly present with extraocular extension and high risk features that results in unsatisfactory treatment and low survival rate. In addition, lack of potential therapeutic and prognostic targets is another challenge in the management of retinoblastoma. We studied comparative proteome of retinoblastoma patients (HPV positive and negative (n=4 each) and controls (n=4), in order to identify potential retinoblastoma-specific protein targets. 2D-DIGE coupled MALDI-TOF/TOF mass spectrometry identified 39 unique proteins. Highly deregulated proteins were GFAP,RBP3,APOA1,CRYAA,CRABP1,SAG and TF. Gene ontology (Panther 7.0) revealed majority of proteins to be associated with metabolic processes (26%) and catalytic activity (38%). 8 proteins were significantly upregulated in HPV positive vis-a-vis HPV negative cases. Patient group exhibited 12 upregulated and 18 downregulated proteins compared to controls. Pathway and network analysis (IPA software) revealed CTNNB1 as most significantly regulated signalling pathway in HPV positive than HPV negative retinoblastoma. The trends in transcriptional change of 9 genes were consistent with those at proteomic level. The Western blot analysis confirmed the expression pattern of RBP3,GFAP and CRABP1. We suggest GFAP,RBP3,CRABP1,CRYAAA,APOA1 and SAG as prospective targets that could further be explored as potential candidates in therapy and may further assist in studying the disease mechanism.
SIGNIFICANCE: In this study we evaluated tumor tissue specimens from retinoblastoma patients and identified 39 differentially regulated proteins compared to healthy retina. From these, we propose RBP3, CRABP1, GFAP, CRYAA, APOA1 and SAG as promising proteomic signatures that could further be explored as efficient prognostic and therapeutic targets in retinoblastoma. The present study is not only a contribution to the ongoing endeavour for the discovery of proteomic signatures in retinoblastoma, but, may also act as a starting point for future studies aimed at uncovering novel targets for further therapeutic interventions and improving patient outcomes.

Oh SH, Kim WY, Lee OH, et al.
Insulin-like growth factor binding protein-3 suppresses vascular endothelial growth factor expression and tumor angiogenesis in head and neck squamous cell carcinoma.
Cancer Sci. 2012; 103(7):1259-66 [PubMed] Free Access to Full Article Related Publications
Angiogenesis, the process by which new blood vessels are recruited to existing ones, is essential for tumor development. Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3), which modulates bioavailability of IGF, has been studied for its potential role in angiogenesis during tissue regeneration and cancer development. In this study, we assessed the role of IGFBP-3 in tumor angiogenesis in head and neck squamous cell carcinoma (HNSCC) and human umbilical vein endothelial cells (HUVECs) using adenoviral (Ad-BP3) and recombinant (rBP3) IGFBP-3. Using an in vivo orthotopic tongue tumor model, we confirmed that both Ad-BP3 and rBP3 suppress the growth of UMSCC38 HNSCC cells in vivo. Ad-BP3 inhibited vascularization in tongue tumors and chorio-allantoic membrane, and suppressed angiogenesis-stimulating activities in UMSCC38 cells. In HUVECs, Ad-BP3 decreased migration, invasion, and tube formation. rBP3 also suppressed production of vascular endothelial growth factor (VEGF) in HUVECs and UMSCC38 cells. IGFBP-3-GGG, a mutant IGFBP-3 with loss of IGF binding capacity, suppressed VEGF production. In addition, we found that IGFBP-3 suppressed VEGF expression, even in mouse embryonic fibroblasts from an IGF-1R-null mouse. Finally, we demonstrated that IGFBP-3-GGG inhibits tumor angiogenesis and growth to the same degree as wild-type IGFBP-3. Taken together, these results support the hypothesis that IGFBP-3 has anti-angiogenic activity in HNSCC, at least in part due to IGF-independent suppression of VEGF production from vascular endothelial cells and cancer cells.

Garcia-Ramírez M, Hernández C, Villarroel M, et al.
Interphotoreceptor retinoid-binding protein (IRBP) is downregulated at early stages of diabetic retinopathy.
Diabetologia. 2009; 52(12):2633-41 [PubMed] Related Publications
AIMS/HYPOTHESIS: Interphotoreceptor retinoid-binding protein (IRBP) plays a major role in the visual cycle and is essential to the maintenance of photoreceptors. The aim of this study was to determine whether a decrease in IRBP production exists in the early stages of diabetic retinopathy.
METHODS: Vitreous samples from diabetic patients with proliferative and non-proliferative diabetic retinopathy (PDR, NPDR), and from non-diabetic patients with macular hole (control group) were selected for IRBP quantitative assessment by proteomic analysis (fluorescence-based difference gel electrophoresis) and western blot. Human post mortem eyes (n = 16) from diabetic donors without clinically detectable retinopathy and from non-diabetic donors (n = 16) were used to determine IRBP (also known as RBP3) mRNA levels (RT-PCR) and protein content (western blot and confocal microscopy). Retinal neurodegeneration was assessed by measuring glial fibrillar acidic protein (GFAP) and the apoptotic rate. Y79 human retinoblastoma cells were used to test the effects of glucose, TNF-alpha and IL-1beta on IRBP expression and IRBP levels.
RESULTS: Intravitreous IRBP concentration was significantly lower in PDR < NPDR < control in proteomic and western blot analysis. IRBP mRNA levels and IRBP protein content were significantly lower in the retinas from diabetic donors than in those from non-diabetic donors. Increased GFAP and a higher degree of apoptosis were observed in diabetic retinas compared with non-diabetic retinas. A dose-dependent downregulation of IRBP mRNA expression and IRBP content was detected with glucose, TNF-alpha and IL-1beta in cultures of Y79 human retinoblastoma cells.
CONCLUSIONS/INTERPRETATION: Underproduction of IRBP is an early event in the human diabetic retina and is associated with retinal neurodegeneration. The mechanisms leading to this deficit deserve further investigation.

Boatright JH, Stodulkova E, Do VT, et al.
The effect of retinoids and butyrate on the expression of CRX and IRBP in retinoblastoma cells.
Vision Res. 2002; 42(8):933-8 [PubMed] Related Publications
We sought to determine whether differentiation agents such as retinoids and butyrate regulate transcript levels of interphotoreceptor retinoid binding protein (IRBP) and cone rod homeobox (CRX), a homeodomain transcription factor that regulates IRBP promoter activity. WERI-Rb1 retinoblastoma cells were treated with all-trans retinol, all-trans retinoic acid, or butyrate. IRBP and CRX mRNA levels were determined by quantitative RT-PCR. Butyrate at low concentrations increased both mRNA levels but suppressed them at higher concentrations. Retinoic acid had minimal effects. Retinol increased CRX mRNA over four fold. IRBP and CRX transcript levels are sensitive to butyrate and CRX expression is sensitive to retinol.

Boatright JH, Borst DE, Stodulkova E, Nickerson JM
Endogenous CRX expression and IRBP promoter activity in retinoblastoma cells.
Brain Res. 2001; 916(1-2):136-42 [PubMed] Related Publications
PURPOSE: To determine whether antisense oligonucleotides (AODNs) targeted against CRX, a photoreceptor-specific trans-acting factor, suppress CRX expression and interphotoreceptor retinoid binding protein (IRBP) promoter activity.
METHODS: Cultures of human retinoblastoma cells were transfected with chloramphenicol acetyltransferase (CAT) reporter plasmids containing a mouse IRBP promoter and AODNs directed against CRX. RT-PCR using primers specific to CRX, OTX2, GAPDH, or RNase H was conducted on total RNA isolated from retinoblastoma cells at various times following transfection with AODNs.
RESULTS: Transfection of retinoblastoma cells with IRBP promoter CAT constructs alone produced high activity. Co-transfection with AODNs suppressed IRBP promoter activity in a concentration-dependent manner, with half-maximal effect produced at about 2 nM AODN concentration. Transfection with CAT constructs containing an SV40 promoter produced high activity that was unaffected by co-transfection with AODNs. RT-PCR products were obtained for all target sequences. CRX RT-PCR product from cells transfected with AODNs was greatly diminished following transfection with an AODN whereas control transcripts, including that of OTX2, were relatively unaffected.
CONCLUSIONS: The CRX-specific AODNs specifically and potently suppressed CRX expression and IRBP promoter activity, as measured by RT-PCR and transient transfection assays, respectively. Little or no effect was seen on controls. These data suggest that endogenous CRX is required for IRBP promoter activity in retinoblastoma cells.

Yamashita N, Nishiuchi R, Oda M, et al.
Molecular detection of metastatic retinoblastoma cells by reverse transcription polymerase reaction for interphotoreceptor retinoid-binding protein mRNA.
Cancer. 2001; 91(8):1568-73 [PubMed] Related Publications
BACKGROUND: In the current study, the authors report a 4 year old girl with disseminated retinoblastoma. To find sensitive and specific molecular markers for detection of retinoblastoma cells in blood and marrow, the authors evaluated three photoreceptor-associated gene transcripts by using reverse transcription polymerase chain reaction (RT-PCR).
METHOD: Samples of bone marrow and blood were obtained from healthy donors and the patient. RT-PCR was performed to detect the cone alpha'-subunit of cGMP phosphodiesterase (cone alpha'-PDE), the rod beta-subunit of cGMP (rod beta-PDE), and the interphotoreceptor retinoid-binding protein (IRBP) gene transcript in RNA extracted from the samples.
RESULTS: While no expression of rod beta-PDE or IRBP was detected in any of the normal samples, expression of cone alpha'-PDE was detected in two out of seven normal marrow samples. Expression of rod beta-PDE was not detected in the patient samples. Expression of IRBP was detected in the patient samples obtained from iliac bone marrow before intensive chemotherapy but not thereafter.
CONCLUSION: RT-PCR for IRBP was a useful method for detecting metastatic retinoblastoma cells as well as for evaluating the therapeutic effects of treatment in this particular case.

El-Remessy AE, Rabie AM, El-Shishtawy MM, et al.
Regulation of interphotoreceptor retinoid-binding protein (IRBP) gene expression by cAMP in differentiated retinoblastoma cells.
Mol Vis. 2000; 6:243-51 [PubMed] Related Publications
PURPOSE: To determine the mechanism of cyclic AMP (cAMP) regulation of the interphotoreceptor retinoid-binding protein (IRBP) gene in retinoblastoma cells.
METHODS: WERI-Rb1 cells pretreated with laminin or grown on poly-D-lysine-coated substratum for three days were treated with forskolin/3-isobutyl-1-methylxanthin (IBMX) or with dimethyl sulfoxide (DMSO). During a time course of 96 h, cell morphologies were determined by light microscopy, cellular cAMP levels measured by radioimmunoassay, and IRBP and b-actin gene expression determined by Northern blot and RNase protection analyses. IRBP expression and b-actin gene expression in these cells were also determined in the presence or absence of actinomycin D or cycloheximide.
RESULTS: After laminin treatment for 3 days, 27-34% of WERI-Rb1 cells differentiated into spindle shapes. Further forskolin treatment in the presence of IBMX for 5 days resulted in many cells exhibiting the formation of long, ramifying, neurite-like processes that were abolished by an inhibitor of protein kinase A. Cells grown on poly-D-lysine-coated substratum treated with forskolin remained undifferentiated. Treatment of laminin-pretreated cells with forskolin/IBMX, but not with DMSO/IBMX, raised the cAMP level 15-fold within the first hour of treatment. Northern blot analysis of these cells showed a rapid increase of IRBP mRNA, but not b-actin mRNA, reaching a maximum of about 3-fold at 6-8 h. A similar increase of IRBP mRNA was observed using RNase protection analysis except that the maximum was observed at 2-4 h. Actinomycin D blocked this IRBP mRNA induction. Cycloheximide had no effect in this induction.
CONCLUSIONS: These results demonstrate that laminin induces WERI-Rb1 cell differentiation and cAMP provokes the formation of long ramifying neurite-like processes. Forskolin selectively induces IRBP gene expression in the laminin-treated cells through a cAMP-mediated pathway without de novo protein synthesis.

Fong SL, Fong WB
Elements regulating the transcription of human interstitial retinoid-binding protein (IRBP) gene in cultured retinoblastoma cells.
Curr Eye Res. 1999; 18(4):283-91 [PubMed] Related Publications
PURPOSE: To identify cis-acting elements and trans-acting factors involved in the expression of human IRBP gene.
METHODS: Transient transfection of WERI-Rb1 and HeLa cells, DNase 1 footprinting, gel mobility-shift assay and yeast one-hybrid system were used to study the regulatory elements that are involved in the expression of human IRBP gene.
RESULTS: A region between -1620 and -1411 was shown to have enhancer properties. Using nuclear extracts from WERI-Rb1 and HeLa cells, four footprints were identified in the proximal promoter region (-206 to +68). The core promoter element IP1 binds to OTX2 in the yeast one-hybrid system. By cotransfecting HeLa cells, OTX2 could transactivate the irbp promoter. The functions of IP2 (from -119 to -86) and IP3 (from -183 to -147) remain to be determined. The region containing the HeLa cell-specific footprint IP4 (from -202 to -180) could silence the OTX2 transactivation of the irbp promoter.
CONCLUSION: The 5'-flanking region of irbp contains an enhancer sequence. The possible silencer upstream from the core promoter may serve to suppress expression of irbp in HeLa cells. When the proximal promoter is used to identify binding proteins in a human retina library by the yeast one hybrid system, nine of the identified clones contained the cDNA sequence for the homeodomain protein OTX2. Since no clones for the homeodomain protein CRX were found, and since OTX2 can transcriptionally activate irbp in normally non-expressing HeLa cells, it is possible that OTX2 rather than CRX is the transcriptional activator for irbp in human photoreceptors.

Oriola J, Hernandez C, Simo R, et al.
Genetic analysis of seven Mediterranean families with multiple endocrine neoplasia type 2A.
Clin Endocrinol (Oxf). 1996; 44(2):207-12 [PubMed] Related Publications
OBJECTIVE: Genetic analysis is now essential for the accurate screening of families with multiple endocrine neoplasia type 2 (MEN2). We present the genetic analyses by both haplotype and direct RET proto-oncogene mutation analysis in seven Mediterranean MEN 2A families and have compared these results with biochemical screening tests and pathological examinations.
DESIGN: Total DNA was extracted from leucocytes. Linkage analysis was performed using five RFLP systems from three loci that flank the MEN2A locus (FNRB, RBP3, D10S15). RET proto-oncogene analysis was carried out by automatic DNA sequencing and adequate digestion of PCR amplified products for exons 10 and 11. Screening for medullary thyroid carcinoma or C-cell hyperplasia was performed by the pentagastrin provocation test. Adrenal medullary function was assessed by measurements of 24-hour urinary excretion of catecholamines and their metabolites. Serum calcium and phosphate measurements were the initial screen for hyperparathyroidism. Serum PTH was determined only if hyperparathyroidism was suggested by the former determinations.
PATIENT: Genetic study was performed in 59 individuals (39 at risk) from seven kindreds of Mediterranean origin with MEN 2A.
RESULTS: Diagnosis by linkage analysis was not possible in 30% of individuals at risk, but RET proto-oncogene analysis identified all these individuals. Mutations of the RET proto-oncogene were detected in exon 10 (codon 618) in one MEN 2A kindred and in exon 11 (codon 634) in the others. The results of direct analysis were concordant with linkage studies in each case. Three individuals from different MEN 2A kindreds, who were subsequently shown not to be gene carriers, had false positive pentagastrin stimulation tests.
CONCLUSION: Biochemical tests can be replaced by direct DNA mutation analysis as the first line screening test in order to identify gene carriers of MEN 2A.

Mead RS, Cowell JK
Molecular characterization of a (1;10)(p22;q21) constitutional translocation from a patient with neuroblastoma.
Cancer Genet Cytogenet. 1995; 81(2):151-7 [PubMed] Related Publications
A constitutional t(1;10)(p22;q21) from a patient with stage IVS neuroblastoma has been isolated in somatic cell hybrids and the position of the breakpoints analyzed. On chromosome 1 the breakpoint lies in a 4-Mbp region flanked by minisatellite marker D1S234 and by D1S188, which lies in the region of F3. The chromosome 10 breakpoint lies between RBP3 and NAKNR below the MEN2 locus. Because, in patients with genetic disease, constitutional translocations frequently interrupt genes which are related to the clinical phenotype this rearrangement has identified two regions which potentially contain genes related to the development of neuroblastoma.

Bernstein SL, Kutty G, Wiggert B, et al.
Expression of retina-specific genes by mouse retinoblastoma cells.
Invest Ophthalmol Vis Sci. 1994; 35(11):3931-7 [PubMed] Related Publications
PURPOSE: Two cell lines derived from ocular tumors of a transgenic mouse expressing the SV40 large T antigen have been established as models of human retinoblastoma. One line, TM, originated from a metastasis, and the other, TE, originated from the primary tumor. The authors compared these two lines with the normal adult mouse eye by analysis of the expression of five photoreceptor cell-specific proteins: IRBP, opsin, rod- and cone-specific transducins, and S-antigen. The authors sought to determine which of these proteins was expressed qualitatively and to examine semi-quantitatively for changes in the levels of expression in the cell lines.
METHOD: Western blot analysis was used to detect photoreceptor-specific intracellular or secreted proteins. Total RNA was prepared from cultured cells or from mouse adult whole eye. Specific messenger levels in total RNA were determined either by northern hybridization analysis or by a semi-quantitative polymerase chain reaction (PCR), coupled to complementary DNA (cDNA) substrates prepared from total RNA.
RESULTS: IRBP was present in the retinoblastoma cell lines and secreted into the medium. Neither S-antigen nor opsin were detectable by immunoblotting. IRBP and cone transducin mRNA were present in both cell lines. In contrast, opsin, rod transducin, and S-Antigen mRNAs were not detectable by PCR. beta-actin was present in the mRNA populations of whole eye and retinoblastoma. SV40 large T antigen mRNA was present only in retinoblastoma cells.
CONCLUSIONS: IRBP and cone transducin expression in mouse retinoblastoma cells is independent of signaling provided directly or indirectly through large T antigen or Rb105 regulatory cascades. The pattern of photoreceptor-specific gene expression is similar to that seen in human retinoblastoma cell lines. These murine-derived cell lines may be useful as a tool to study IRBP and cone transducin expression in vitro and to determine early retinoblast expression patterns in the mouse.

Lopes MB, Gonzalez-Fernandez F, Scheithauer BW, VandenBerg SR
Differential expression of retinal proteins in a pineal parenchymal tumor.
J Neuropathol Exp Neurol. 1993; 52(5):516-24 [PubMed] Related Publications
The pineal gland and retina share histogenetic features that reflect a similar neurosensory/photosensory ontogeny. Pineal parenchymal tumors demonstrate a highly variable and incomplete photosensory differentiation evidenced by specific cytoarchitectural features and the expression of photosensory retinal S-Antigen (S-Ag). Despite these neuro-ontogenetic parallels, pineal parenchymal tumors have not been well studied for the neuroretinal phenotypes that accompany normal neuroretinal development. The investigation of photoreceptor gene expression may provide an important insight into the histogenesis of pineal parenchymal neoplasms. In this study, a pineal parenchymal tumor of the "mixed pineoblastoma/pineocytoma" type was examined for the expression of several photoreceptor, glial and neuronal proteins including: interphotoreceptor retinoid-binding protein (IRBP), rod opsin, cone opsin, S-Ag and cellular retinaldehyde-binding protein (CRA1BP). The detection of IRBP and its mRNA, the earliest photoreceptor-associated protein expressed during retinal development, corroborated the rudimentary photosensory differentiation of this tumor which had limited cytoarchitectural evidence for pineal differentiation. The analysis of IRBP expression may facilitate the diagnostic recognition of primitive pineal neoplasms and further define the neuroretinal differentiation which occurs in pineal parenchymal tumors.

Brooks-Wilson AR, Lichter JB, Ward DC, et al.
Genomic and yeast artificial chromosome long-range physical maps linking six loci in 10q11.2 and spanning the multiple endocrine neoplasia type 2A (MEN2A) region.
Genomics. 1993; 17(3):611-7 [PubMed] Related Publications
Multiple endocrine neoplasia types 2A and 2B (MEN 2A and MEN 2B) and familial medullary thyroid carcinoma (FMTC) are dominantly inherited cancers that have in common the clinical feature of medullary thyroid carcinoma (MTC). We have performed both genomic long-range restriction mapping and yeast artificial chromosome (YAC) contig assembly and restriction mapping to establish physical linkage, order, and distances between six loci in 10q11.2 near the genes responsible for these hereditary cancers. RET, D10S94, D10S182, and D10S102 have been mapped in genomic DNA. RET, D10S94, D10S182, D10F38S3, and the 10q11.2 sequences detected by DNA marker DM124 are encompassed by a 1-Mb YAC contig. Six physically linked loci are within 1.4 Mb and have an order and orientation of 10cen, D10F38S3, DM124, RET, D10S94, D10S182, D10S102, 10qter. Mutations in the RET proto-oncogene have recently been demonstrated to be associated with MEN 2A and FMTC. RET is located within a genetically defined MEN2A candidate interval between D10S141 and D10S94; MEN2B has been mapped to a larger, overlapping region between D10S141 and a more distal locus, RBP3. Both our genomic physical map and our YAC contig span the entire MEN2A candidate region and overlap with that of MEN2B. These maps will facilitate the identification of genes that can be considered candidates for MEN2B and the identification of tumor-specific alterations important in sporadic MTC.

Gardner E, Papi L, Easton DF, et al.
Genetic linkage studies map the multiple endocrine neoplasia type 2 loci to a small interval on chromosome 10q11.2.
Hum Mol Genet. 1993; 2(3):241-6 [PubMed] Related Publications
We have carried out genetic linkage analyses using fifteen polymorphic loci in the pericentromeric region of chromosome 10 in families with the inherited cancer syndromes multiple endocrine neoplasia (MEN) type 2A or 2B. A highly polymorphic microsatellite from the locus D10S141 in q11.2 was found to be recombinant with respect to the disease locus in two individuals and defines a new proximal flanking marker for both MEN2A and 2B. An additional recombination provides evidence that the locus D10S94, also in q11.2, is the closet distal flanking marker for MEN2A. This localises the MEN2A gene to a small region of 10q11.2 flanked by the loci D10S141 and D10S94, which are separated by a sex-averaged genetic distance of 0.55 cM. The MEN2B gene maps to a larger region, flanked by D10S141 and RBP3.

Lichter JB, Wu J, Brooks-Wilson AR, et al.
A new polymorphic marker (D10S97) tightly linked to the multiple endocrine neoplasia type 2A (MEN2A) locus.
Hum Genet. 1993; 90(5):516-20 [PubMed] Related Publications
Familial multiple endocrine neoplasia type 2A (MEN 2A) is a cancer syndrome that is inherited as an autosomal dominant with high penetrance. Its clinical features are medullary carcinoma of the thyroid, pheochromocytomas, and hyperparathyroidism. A new polymorphic locus D10S97 (probe: KW6 delta SacI) detects a codominant EcoRI polymorphism that is tightly linked to the MEN2A locus. The peak lod score for linkage between D10S97 with MEN2A is 13.03 at theta = 0.00. The polymorphic locus D10S97 maps, by linkage analysis, into the previously defined interval between FNRB and RBP3 to which MEN2A has been assigned. We present physical mapping data showing that the probe pKW6 originates from 10p13 and that the polymorphic locus D10S97 in 10q11.2 is detected by cross-hybridization.

Howe JR, Lairmore TC, Mishra SK, et al.
Improved predictive test for MEN2, using flanking dinucleotide repeats and RFLPs.
Am J Hum Genet. 1992; 51(6):1430-42 [PubMed] Free Access to Full Article Related Publications
Gene(s) for the autosomal dominant endocrine cancer syndromes, multiple endocrine neoplasia type 2A (MEN2A), multiple endocrine neoplasia type 2B (MEN2B), and familial medullary thyroid carcinoma (MTC1) all map to the pericentromeric region of chromosome 10. Predictive testing for the inheritance of mutant alleles in individuals at risk for these disorders has been limited by the availability of highly informative and closely linked flanking markers. We describe the development of eight new markers, including two PCR-based dinucleotide repeat polymorphisms and six RFLPs that flank the disease loci. One of the dinucleotide repeat markers (sJRH-1) derives from the RBP3 locus on 10q11.2 and has a PIC of .88. The other dinucleotide repeat (sTCL-1) defines a new locus, D10S176, that maps by in situ hybridization to 10p11.2 and has a PIC of .68. We have constructed a new genetic linkage map of the pericentromeric region of chromosome 10, on the basis of 13 polymorphisms at six loci, which places the MEN2A locus between the dinucleotide repeat markers, with odds of 5,750:1 over the next most likely position. Using this set of markers, predictive genetic testing of 130 at-risk individuals from six families segregating MEN2A revealed that 95% were jointly informative with flanking markers, representing a significant improvement in genetic testing capabilities.

al-Ubaidi MR, Font RL, Quiambao AB, et al.
Bilateral retinal and brain tumors in transgenic mice expressing simian virus 40 large T antigen under control of the human interphotoreceptor retinoid-binding protein promoter.
J Cell Biol. 1992; 119(6):1681-7 [PubMed] Free Access to Full Article Related Publications
We have previously shown that postnatal expression of the viral oncoprotein SV40 T antigen in rod photoreceptors (transgene MOT1), at a time when retinal cells have withdrawn from the mitotic cycle, leads to photoreceptor cell death (Al-Ubaidi et al., 1992. Proc. Natl. Acad. Sci. USA. 89:1194-1198). To study the effect of the specificity of the promoter, we replaced the mouse opsin promoter in MOT1 by a 1.3-kb promoter fragment of the human IRBP gene which is expressed in both rod and cone photoreceptors during embryonic development. The resulting construct, termed HIT1, was injected into mouse embryos and five transgenic mice lines were established. Mice heterozygous for HIT1 exhibited early bilateral retinal and brain tumors with varying degrees of incidence. Histopathological examination of the brain and eyes of three of the families showed typical primitive neuroectodermal tumors. In some of the bilateral retinal tumors, peculiar rosettes were observed, which were different from the Flexner-Wintersteiner rosettes typically associated with human retinoblastomas. The ocular and cerebral tumors, however, contained Homer-Wright rosettes, and showed varying degrees of immunoreactivity to antibodies against the neuronal specific antigens, synaptophysin and Leu7, but not to antibodies against photoreceptor specific proteins. Taken together, the results indicate that the specificity of the promoter used for T antigen and/or the time of onset of transgene expression determines the fate of photoreceptor cells expressing T antigen.

Gonzalez-Fernandez F, Lopes MB, Garcia-Fernandez JM, et al.
Expression of developmentally defined retinal phenotypes in the histogenesis of retinoblastoma.
Am J Pathol. 1992; 141(2):363-75 [PubMed] Free Access to Full Article Related Publications
Retinoblastoma, the most common intraocular tumor of childhood, is a malignant neoplasm that arises during retinal development. The embryonal cell target for neoplastic transformation is not yet clearly defined. To better understand the histogenetic potential of this tumor, the expression of photoreceptor and glial cell-associated proteins were examined in 22 primary retinoblastomas. Interphotoreceptor retinol-binding protein (IRBP), cone and rod opsins were selected as the photoreceptor specific proteins due to their different temporal patterns of expression during normal retinal development. Neoplastic Müller cell differentiation, and non-neoplastic reactive astrocytes were identified using cellular retinaldehyde binding-protein (CRAlBP), and glial fibrillary acidic protein (GFAP), respectively. Photoreceptor proteins were present in 16 cases and showed different cellular patterns of expression. IRBP and cone opsin were usually abundant. Although rod opsin was clearly identified in eight tumors, its expression was more restricted than either IRBP or cone opsin. This differential pattern of expression, opposite to the normal pattern of photoreceptor gene expression in the adult retina, corresponded to a marked decrease in mRNA for rod opsin. Cone opsin and IRBP colocalized in fleurettes demonstrating that neoplastic human cone cells are capable of IRBP synthesis. Müller cell differentiation was present in 12 of the 16 cases in which photoreceptor proteins were detected. In contrast, GFAP was only present in reactive, stromal astrocytes associated with blood vessels. Our data suggest that the retinoblastoma has the histogenetic potential of the immature neural retinal epithelium which can give rise to both photoreceptor and Müller cell lineages. The differential expression of cone and rod phenotypes in retinoblastoma is consistent with the "default" mechanism of cone cell differentiation.

Miller DL, Dill FJ, Lichter JB, et al.
Isolation and high-resolution mapping of new DNA markers from the pericentromeric region of chromosome 10.
Genomics. 1992; 13(3):601-6 [PubMed] Related Publications
The gene responsible for multiple endocrine neoplasia type 2A (MEN 2A) has been localized to the pericentromeric region of chromosome 10. Several markers that fail to recombine with MEN2A have been identified, including D10Z1, D10S94, D10S97, and D10S102. Meiotic mapping in the MEN2A region is limited by the paucity of critical crossovers identified and by the dramatically reduced rates of recombination in males. Additional approaches to mapping loci in the pericentromeric region of chromosome 10 are required. We have undertaken the generation of a detailed physical map by radiation hybrid mapping. Here we report the development of a radiation hybrid panel and its use in the mapping of new DNA markers in pericentromeric chromosome 10. The radiation-reduced hybrids used for mapping studies all retain small subchromosomal fragments that include both D10S94 and D10Z1. One hybrid was selected as the source of DNA for cloning. One hundred five human recombinant clones were isolated from a lambda library made with pp11A DNA. We have completed regional mapping of 22 of those clones using our radiation hybrid mapping panel. Seven markers have been identified and, when taken together with previously meiotically mapped markers, define eight radiation hybrid map intervals between D10S34 and RBP3. The identical order is found for a number of these using either the radiation hybrid mapping panel or the meiotic mapping panel. We believe that this combination cloning and mapping approach will facilitate the precise positioning of new markers in pericentromeric chromosome 10 and will help in refining further the localization of MEN2A.

Rodrigues MM, Rajagopalan S, Lee L, et al.
Retinoblastoma: messenger RNA for interphotoreceptor retinoid binding protein.
Curr Eye Res. 1992; 11(5):425-33 [PubMed] Related Publications
Surgically excised retinoblastomas from 14 patients (age range nine months to two years) were assessed by immunocytochemistry for the expression of photoreceptor-specific proteins and neuronal and glial cell markers. Adjacent tissues were examined for messenger RNA expression of interphotoreceptor retinoid-binding protein (IRBP) using Northern blots. For immunocytochemical stains (ABC method), monoclonal and polyclonal antibodies included S-Ag, rhodopsin, neuron specific enolase (NSE), glial fibrillary acidic protein (GFAP), IRBP, neural adhesion molecule (N-CAM), and rod and cone specific transducin (TR alpha and TC alpha). Histopathology revealed mostly poorly differentiated tumors with necrosis and lack of Flexner-Wintersteiner rosettes. Immunocytochemical staining showed focal IRBP expression in one of the tumors and S-antigen in two cases. Immunoreactivity with rhodopsin was negative. N-CAM, a neural adhesive protein which appears to be involved in the regulation of adhesive interaction during neuronal differentiation, was positive except in two cases. All tumors showed immunoreactivity with NSE, whereas GFAP staining was limited to the perivascular glial tissue confirming the essential neuronal nature of retinoblastoma cells. TC alpha was detected in all tumors and TR alpha in one case. Messenger RNA for IRBP was detected in tumors in which IRBP immunoreactivity could not be detected.

Shimotake T, Iwai N, Yanagihara J, et al.
Prediction of affected MEN2A gene carriers by DNA linkage analysis for early total thyroidectomy: a progress in clinical screening program for children with hereditary cancer syndrome.
J Pediatr Surg. 1992; 27(4):444-6 [PubMed] Related Publications
The gene predisposing to multiple endocrine neoplasia type 2A (MEN 2A) has been assigned to chromosome 10, and affected gene carriers can be identified before the development of associated malignancy in some informative families. We applied these advances in gene mapping to clinical screening for possible pediatric surgery. A family with MEN 2A, consisting of 88 members and their spouses, was studied to test the reliability of the provocation of plasma calcitonin with pentagastrin and the possibility of DNA diagnosis of mutated gene carriers with DNA probes closely linked to the MEN2A gene including RBP3 and FNRB genes. Nineteen of the 88 were diagnosed as MEN 2A carriers. Twelve of them were treated surgically and the others died of medullay thyroid carcinoma (MTC) or pheochromocytoma. A strikingly sensitive response of calcitonin was observed in all those with MTC. The genotypes cosegregating with the abnormal allele at MEN2A in this family could be deduced from clinically established affected members. The early detection of gene carriers allows us to concentrate our screening efforts on children at high risk and to release non gene carriers from repeated unnecessary testing. MEN2A is one of the first cancer syndromes for which DNA screening permits early detection of members at high risk.

Yamamoto S, Morimoto I, Fujihira T, et al.
A kindred of multiple endocrine neoplasia type 2B.
Endocrinol Jpn. 1992; 39(1):25-30 [PubMed] Related Publications
We describe familial cases of multiple endocrine neoplasia (MEN) 2B: A 48-year-old man is the proband. He had pheochromocytoma, medullary thyroid carcinomas (MTCs), parathyroid hyperplasia, mucosal neuromas, eversion of eyelids and Marfanoid appearance, and then underwent adrenalectomy and total thyroidectomy. Family screening revealed that his two daughters (10 and 8 years old) had mucosal neuromas and increased serum calcitonin (CT). Both of them had MTCs but no pheochromocytoma, and their MTCs were surgically removed. The father and his children have been in favorable condition since the operations. Southern blot analysis with 33 polymorphic DNA probes was done in MTCs obtained from two daughters. An RBP3 (10q11.2) locus linked to a predisposing gene on chromosome 10 was uninformative in either patient because of constitutional homozygosity. Loss of heterozygosity at the MYCL1 locus on chromosome 1p32 was observed in MTC from the younger sister, but no loss of heterozygosity was recognized in other loci examined. Deletion of the 1p32 locus may play a role in the development of MEN 2B.

Lairmore TC, Howe JR, Dou S, et al.
Isolation of YAC clones from the pericentromeric region of chromosome 10 and development of new genetic markers linked to the multiple endocrine neoplasia type 2A gene.
Henry Ford Hosp Med J. 1992; 40(3-4):210-4 [PubMed] Related Publications
Genetic linkage mapping and contig assembly using yeast artificial chromosome (YAC) technology form the basis of our strategy to clone and define the genomic structure of the pericentromeric region of chromosome 10 containing the multiple endocrine neoplasia type 2A gene. Thus far YAC walks have been initiated from five chromosome 10 pericentromeric loci including RBP3, D10S94, RET, D10Z1, and FNRB. Long range pulsed-field gel electrophoresis maps are constructed from the YACs isolated to define clone overlaps and to identify putative CpG islands. Bidirectional YAC walks are continued by rescreening the YAC library with sequence-tagged site assays developed from end-clones. Several new restriction fragment length polymorphisms and simple sequence repeat polymorphism markers have been identified from the YAC clones. In particular, two highly informative (CA)n dinucleotide repeat markers, sTCL-1 from proximal chromosome 10p (16 alleles, PIC = 0.68) and sJRH-1 from the RBP3 locus (18 alleles, PIC = 0.88), provide useful reagents for a polymerase chain reaction-based predictive genetic test that can be performed rapidly from small amounts of DNA.

Jackson CE, Norum RA
Genetics of the multiple endocrine neoplasia type 2B syndrome.
Henry Ford Hosp Med J. 1992; 40(3-4):232-5 [PubMed] Related Publications
Multiple endocrine neoplasia type 2B (MEN 2B) is similar to MEN 2A in that both autosomal dominant syndromes include medullary thyroid cancers and pheochromocytomas. It is distinct in that MEN 2B patients have much earlier age of onset with more aggressive tumors and mucosal neuromas of the lips and tongue. The neuromas allow ascertainment generally before age 5. Studies of two and three generations of 14 MEN 2B families disclosed close linkage of the MEN 2B gene to DNA markers to which MEN2A had been linked. Multipoint analysis utilizing additional results in three generations of a 15th family have disclosed a peak total lod score of 8.89 at the midpoint between the centromere markers D10Z1 and RBP3 on the long arm (band q11). One recombinant was observed between D10Z1 and MEN2B, but this individual was not recombinant with D10S94. These studies suggest physical proximity of MEN2A and MEN2B but do not establish allelism for the gene(s).

Lamothe EM, Narod SA, Miller S, et al.
Screening for multiple endocrine neoplasia type 2A with DNA-polymorphism analysis.
Henry Ford Hosp Med J. 1992; 40(3-4):224-6 [PubMed] Related Publications
Nine chromosome 10 DNA markers (FNRB, D10S34, D10Z1, MEN203, D10S94, RBP3, D10S15, MBP [48.11], D10S22) were typed in two large Canadian pedigrees with multiple endocrine neoplasia type 2A (MEN 2A). These markers and the gene for MEN 2A (MEN2A) are believed to be in one linkage group spanning approximately 15 cM (male). MEN203 and D10S94 were informative and tightly linked to MEN2A with no recombinants observed in 26 meiotic events. D10S15 (MCK2), widely used in DNA genotyping predictions, demonstrated two recombinants in these two families. The use of multiple flanking markers increases both the likelihood of informativeness and the accuracy of risk assessments for predictive testing. We were able to assign a risk estimate for all 10 at-risk individuals.

Ward JL, Hyland VJ, Andrew DS, et al.
Medullary thyroid carcinoma: Australian experience with genetic testing.
Henry Ford Hosp Med J. 1992; 40(3-4):220-3 [PubMed] Related Publications
Linkage analysis has been performed in four pedigrees with multiple endocrine neoplasia type 2A (MEN 2A) or familial medullary thyroid carcinoma (MTC) using pericentromeric chromosome 10 probes. Important information regarding carrier status has been provided in 10 individuals, many of whom would not have been identified by pentagastrin stimulation testing. We have also used pulsed field gel electrophoresis (PFGE) to link the probes H4.IRBP and pMCK2 to a 150 kb fragment. Using PFGE, no evidence was found in DNA from lymphocytes of a major DNA rearrangement in two individuals affected with MEN 2A and an individual with MEN 2B compared with normals. Metastatic MTC from one patient has been used to generate a cDNA library which will be used to screen for candidate MEN 2A and MEN 2B gene(s).

Tanaka N, Yamamoto M, Miki T, et al.
Preclinical detection of MEN 2A gene carrier using linked DNA markers.
Jinrui Idengaku Zasshi. 1991; 36(2):165-70 [PubMed] Related Publications
We have performed preclinical risk estimation of multiple endocrine neoplasia type 2A (MEN 2A) by using the polymorphic DNA markers tightly linked to the MEN2A locus. The gene for MEN 2A has been assigned to the pericentromeric region of chromosome 10 by linkage analysis. The preclinical detection of gene carriers in MEN 2A families using tightly linked DNA markers is useful for surgical treatment at an early stage. The DNA markers, RBP3 (retinol-binding protein 3, interstitial) and FNRB (fibronectin receptor, beta polypeptide), are both tightly linked to the MEN2A locus, and are localized to opposite sides of the MEN2A locus. We have used RBP3 and FNRB as markers for preclinical diagnosis. Of 18 Japanese families with MEN 2A, 6 families are informative for both loci, and other 10 families are informative for either RBP3 or FNRB. In one informative family, a 20-year-old female is predicted to be the gene carrier (probability; about 99%). She should be carefully followed up till full penetrance age. We conclude that DNA-based prediction of MEN 2A is an effective procedure for clinical use.

Lairmore TC, Howe JR, Korte JA, et al.
Familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2B map to the same region of chromosome 10 as multiple endocrine neoplasia type 2A.
Genomics. 1991; 9(1):181-92 [PubMed] Related Publications
Medullary thyroid carcinoma (MTC) occurs as a component of three well-described autosomal dominant familial cancer syndromes. Multiple endocrine neoplasia type 2A (MEN 2A) is characterized by MTC, pheochromocytomas, and parathyroid hyperplasia. Patients with the rarer multiple endocrine neoplasia type 2B (MEN 2B) syndrome develop MTC and pheochromocytomas, as well as mucosal neuromas, ganglioneuromatosis of the gastrointestinal tract, and a characteristic "marfanoid" habitus. Finally, MTC is transmitted in an autosomal dominant pattern in some families without associated pheochromocytomas or parathyroid hyperplasia (familial medullary thyroid carcinoma, MTC1(2). Sixty-one members of two well-characterized kindreds segregating MTC1 and 34 [corrected] members of six families segregating MEN2B were genotyped using a panel of RFLP probes from the pericentromeric region of chromosome 10 near a locus for MEN 2A. Statistically significant linkage was observed between the chromosome 10 centromere-specific marker D10Z1 and MTC1 (maximum pairwise lod score 5.88 with 0% recombination) and D10Z1 and MEN2B (maximum pairwise lod score 3.58 with 0% recombination). A maximum multipoint lod score of 4.08 was obtained for MEN2B at the position of D10Z1. In addition, 92 members of a previously unreported large MEN2A kindred were genotyped, and linkage to the pericentromeric region of chromosome 10 is reported (maximum pairwise lod score of 11.33 with 0% recombination between MEN2A and RBP3). These results demonstrate that both a locus for familial MTC and a locus for MEN 2B map to the pericentromeric region of chromosome 10, in the same region as a locus for MEN 2A. The finding that each of these three clinically distinct familial cancer syndromes maps to the same chromosomal region suggests that all are allelic mutations at the same locus or represent a cluster of genes involved in the regulation of neuroendocrine tissue development.

Tanaka N, Miki T, Yamamoto M, et al.
Mapping of the genes around MEN2A locus using pulsed-field gel electrophoresis.
Jinrui Idengaku Zasshi. 1990; 35(4):325-30 [PubMed] Related Publications
The gene for multiple endocrine neoplasia type 2A (MEN 2A) is closely linked to RBP3 (retinol-binding protein 3, interstitial, probe IRBP.H4) and the DNA marker D10S15 (probe pMCK2), which have been assigned to the proximal long arm of chromosome 10 by linkage analysis both in Caucasian and Japanese populations. We have constructed a rare-cutting restriction map around the RBP3 and D10S15 loci by pulsed-field gel electrophoresis (PFGE). The RBP3 and D10S15 loci appeared to be within a single 160 kb MluI fragment. In 5 patients with MEN 2A, gene rearrangements, such as a gross deletion, were not found in the 880 kb NruI fragment which covered the closest region to the MEN-2A locus from the RBP3 and D10S15 loci.

Carson NL, Wu JS, Jackson CE, et al.
The mutation for medullary thyroid carcinoma with parathyroid tumors (MTC with PTs) is closely linked to the centromeric region of chromosome 10.
Am J Hum Genet. 1990; 47(6):946-51 [PubMed] Free Access to Full Article Related Publications
Two new morphs (F and G) detected by the centromeric alpha satellite probe p alpha 10RP8 and D10Z1 in HinfI digests are linked to the PstI polymorphisms of D10Z1, confirming their chromosome 10 location. The F and G morphs were in strong linkage disequilibrium with each other but were in weak linkage disequilibrium with the A and B morphs defined in PstI digests. Data for haplotypes formed by using the A and F morphs improved the lod score for linkage between the disease locus for multiple endocrine neoplasia type 2A (MEN2A) and D10Z1 (Z = 14.06 at theta = 0) in the six large families studied by Wu et al. Furthermore, the locus that codes for a distinct phenotype, medullary thyroid carcinoma (MTC) with parathyroid tumors (PTs) and no pheochromocytomas (PHEOs) (referred to as MTC with PTs), in one of the families was closely linked to two markers, D10Z1 and RBP3, with lodscores of 2.86 and 3.54, respectively, at theta = 0. A possible allelic association was noted between disease phenotypes and centromeric haplotypes. The phenotype MTC and PHEOs with and without PTs was associated with the same relatively common centromeric haplotype (A + B-F-G-) in the four families in which all four morphs could be determined, while the phenotype MTC with PTs was associated with the rare centromeric haplotype (A-B-F-G+) in one family.

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