Disease relevance of NRL

• Recessive NRL mutations in patients with clumped pigmentary retinal degeneration and relative preservation of blue cone function [1].
• Because of its specific pattern of expression, NRL is a candidate gene for retinal diseases [2].
• PURPOSE: To determine if mutations in the retinal transcription factor gene NRL are associated with retinopathies other than autosomal dominant retinitis pigmentosa (adRP) [3].
• Here, we show that retinoic acid (RA), a diffusible factor implicated in rod development, activates the expression of NRL in serum-deprived Y79 human retinoblastoma cells and in primary cultures of rat and porcine photoreceptors [4].
• We have previously shown that neu oncogene-initiated rat mammary carcinomas uniquely over-express neu-related lipocalin (NRL), a member of the calycin protein superfamily [5].

High impact information on NRL

• A mutation in NRL is associated with autosomal dominant retinitis pigmentosa [6].
• Our studies establish that NRL is not only essential but is sufficient for rod differentiation and that postmitotic photoreceptor precursors are competent to make binary decisions during early retinogenesis [7].
• From the Cover: Transformation of cone precursors to functional rod photoreceptors by bZIP transcription factor NRL [7].
• Ectopic expression of NRL in developing cones can also induce rod-like characteristics and partially suppress cone-specific gene expression [7].
• Our report presents an unusual clinical phenotype in humans with loss-of-function mutations in NRL [1].

Chemical compound and disease context of NRL

• The authors investigated the prevalence of immediate (Type I) hypersensitivity to gloves made from natural rubber latex, or NRL, by performing skin-prick tests on 2,166 dental workers over the course of a two-year period (with two one-year intervals) [8].
• As with clonidine, it evokes hypotension when injected into the NRL region and it completely displaces the [3H]clonidine bound to specific imidazoline-binding sites in human medullary membrane preparations, but it has proved more selective for cerebral imidazoline receptors than clonidine [9].

Biological context of NRL

• In transient transfection experiments, the mutant protein showed significantly reduced ability to transactivate the rhodopsin promoter, as well as lower synergistic activation with the bZIP transcription factor NRL [10].
• Interestingly, the mapped CRX transactivation domains were also critical when coexpressed with NRL [11].
• Here we report that six isoforms of NRL (29-35 kDa) are generated by phosphorylation and expressed specifically in the mammalian retina [12].
• Loss-of-function NRL alleles have not been described previously in humans, but since the same mutation was present in unaffected family members, it raises the possibility that the abnormal ESCS phenotype in Patient A may result from a digenic mechanism, with a heterozygous NRL mutation and a mutation in another unknown gene [13].
• NRL is expressed in postmitotic neuronal cells and in lens during embryonic development, but exhibits a retina-specific pattern of expression in the adult [14].

Anatomical context of NRL

• FIZ1 is expressed during photoreceptor maturation, and synergizes with NRL and CRX at rod-specific promoters in vitro [15].
• These findings support previous evidence that FIZ1 is present in rod-photoreceptors (co-immunoprecipitation from nuclear-protein extracts with rod-specific NRL) [15].
• The NRL gene maps to human chromosome 14 by Southern blot analysis of genomic DNA from a human-rodent somatic cell hybrid panel [2].
• Here, we characterize the putative human homolog of NRL, neutrophil gelatinase-associated lipocalin (NGAL). ngal gene expression was found at moderate levels in only 2 of 17 human tissues examined, breast and lung [5].
• NRL was particularly enriched in prehypertrophic chondrocytes [16].

Associations of NRL with chemical compounds

• Deletion analysis revealed that the CRX homeodomain (CRX-HD) plays an important role in the interaction with the NRL leucine zipper [17].
• Using the yeast two-hybrid method and glutathione S-transferase pull-down assays, we demonstrate that the leucine zipper of NRL can physically interact with CRX [17].
• We also describe the production of another NRL allergen with the system, Hev b1, which formed large aggregates and gave small yields in purification [18].
• The monoamine oxidase (MAO) inhibitor tranylcypromine (TCP) (1 nM-10 microM), markedly enhanced [3H]BFI binding in both NRL and cortex [19].
• BACKGROUND: Immunological cross-reactivity between gutta-percha and natural rubber latex, or NRL, has not been demonstrated clearly despite recent concerns and several suspected cases reported in the literature [20].

Regulatory relationships of NRL

• Mutation screening of patients with Leber Congenital Amaurosis or the enhanced S-Cone Syndrome reveals a lack of sequence variations in the NRL gene [3].

Other interactions of NRL

• A reciprocal deletion analysis showed that the leucine zipper of NRL is required for interaction with CRX-HD [17].
• RESULTS: NR2E3 expression was detected shortly after the appearance of NRL in putative immature rods on the foveal edge at Fwk 11 [21].
• NRL and TBP could be co-immunoprecipitated from bovine retinal nuclear extract [22].
• METHODS: The coding regions of the NR2E3 and NRL genes and part of the THRB1 coding region were scanned for mutations using single-strand conformation and direct sequencing methods [23].
• Interestingly, unlike NRL in rat mammary carcinomas, no significant association between NGAL expression and HER-2/neu activation was found in human breast tumors [5].

Analytical, diagnostic and therapeutic context of NRL

• In both human retinal cell cultures and sections of fetal and adult human retina, NRL is present in the nuclei of developing and mature rods but not cones [12].
• Both NR2E3 and NRL expression patterns were followed by immunocytochemistry [21].
• Human bZIP transcription factor gene NRL: structure, genomic sequence, and fine linkage mapping at 14q11.2 and negative mutation analysis in patients with retinal degeneration [14].
• All samples were subjected to heteroduplex analysis of the three exons of the NRL gene, and HphI restriction digest analysis of exon 2 (to identify the S50T mutation) [24].
• An indirect competitive immunoassay has been developed using the NRL array biosensor, offering rapid, sensitive detection and quantification of AFB(1) in buffer, corn and nut products [25].

References