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PubMed1989

The keratin BIIIB gene family: isolation of cDNA clones and structure of a gene and a related pseudogene.

The nucleotide sequence of cDNA clones encoding the three major BIIIB high-sulfur wool keratin proteins (BIIIB2, 3, and 4) and the structure of a BIIIB4 gene and a BIIIB3 pseudogene are reported. Although Southern blot analysis indicates that the BIIIB genes comprise a multigene family in the sheep genome, they are poorly represented in genomic DNA libraries. The family sequence homology of the coding region extends into the 5' and 3' untranslated regions and the near 5' flanking region of the BIIIB3 and 4 genes. These homologies suggest that the BIIIB3 and 4 genes represent the latest gene duplication event in the evolution of the BIIIB multigene family. Like the genes coding for other wool keratin matrix protein components, the BIIIB genes have the conserved 18-bp sequence immediately 5' to the initiation codon and also appear to lack introns.

Amino Acid Sequence↗
PubMed1991

Characterization and chromosomal mapping of a human steroid 5 alpha-reductase gene and pseudogene and mapping of the mouse homologue.

The enzyme steroid 5 alpha-reductase catalyzes the conversion of testosterone into the more powerful androgen, dihydrotestosterone. We previously described the cloning of rat and human cDNAs that encode steroid 5 alpha-reductase and their expression in oocytes and cultured cells. Here, we report the isolation, characterization, and chromosomal mapping of two human steroid 5 alpha-reductase genes. One gene (symbol SRD5A1) is functional, contains five exons separated by four introns, and maps to the distal short arm of chromosome 5. Two informative restriction fragment length polymorphisms are present in exons 1 and 2 of this gene. A second gene (symbol SRD5AP1) has all of the hallmarks of a processed pseudogene and was mapped to the q24-qter region of the X chromosome. In the mouse, a single steroid 5 alpha-reductase gene (Srd5 alpha-1) is linked to Xmv-13 on chromosome 13.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1991

A pseudogene on the X chromosome for the human trifunctional enzyme MTHFD (methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase).

The human trifunctional folate-dependent protein MTHFD has been mapped to chromosome 14q24 and to the X chromosome was identified by screening an X-chromosome-specific library. Amplification by the polymerase chain reaction (PCR) and sequencing of PCR products indicate that the sequence is an intronless pseudogene.

Aminohydrolases↗
PubMed1992

Characterization of human adenylate kinase 3 (AK3) cDNA and mapping of the AK3 pseudogene to an intron of the NF1 gene.

We have isolated cDNA clones for human adenylate kinase isozyme 3 (AK3) with a genomic probe from the neurofibromatosis type 1 (NF1) region. Three overlapping clones isolated from a human frontal-cortex cDNA library gave rise to a consensus sequence of 1.7 kb. The open reading frame identified in this sequence predicted a peptide of 223 residues. A database search revealed striking homology, about 58% amino acid sequence identity, between this predicted protein and bovine AK3. Human AK3 protein also showed significant homology to other members of the adenylate kinase family isolated from various species. Genomic Southern analysis suggested that multiple AK3 loci exist in the human genome, including one located in an intron of NF1 on chromosome 17. The chromosome-17 locus appears to be a processed pseudogene, since it is intronless and contains a polyadenylate tract; it nevertheless retains coding potential because the open reading frame is not impaired by any observed base substitutions.

Adenylate Kinase↗
PubMed1992

Sequence organization of variant mouse 4.5 S RNA genes and pseudogenes.

The rodent 4.5 S RNA is an RNA polymerase III product with a sequence related to the Alu family of interspersed repeated DNA. A previous study identified a tandem array of 4.2-kb repeating units that contain the 4.5 S RNA coding sequence as well as many short repetitive sequences. To understand the genomic organization of this gene family, we have isolated and characterized 4.5 S RNA sequences that are part of the tandem array as well as identified members that are not part of the array. One variant 4.5 S RNA gene family member exhibits length polymorphisms in its minisatellite sites relative to the single previously reported gene. The 4.5 S RNA sequences that are not part of the tandem array possess many of the features of processed pseudogenes and are found adjacent to other interspersed repeated elements. These findings suggest that the mouse 4.5 S RNA can behave as a retroposon, resulting in the accumulation of 4.5 S RNA-like elements at many sites in the genome.

Animals↗
PubMed1995

Molecular cloning and chromosomal localization of a pseudogene related to the human acyl-CoA binding protein/diazepam binding inhibitor.

The acyl-CoA binding protein (ACBP) and the diazepam binding inhibitor (DBI) or endozepine are independent isolates of a single 86-amino-acid, 10-kDa protein. ACBP/DBI is highly conserved between species and has been identified in several diverse organisms, including human, cow, rat, frog, duck, insects, plants, and yeast. Although the genomic locus has not yet been cloned in humans, complementary DNA clones with different 5' ends have been isolated and characterized. These cDNA clones appear to be encoded by a single gene. However, Southern blot analyses, in situ hybridizations, and somatic cell hybrid chromosomal mapping all suggest that there are multiple ACBP/DBI-related sequences in the genome. To identify potential members of this gene family, degenerate oligonucleotides corresponding to highly conserved regions of ACBP/DBI were used to screen a human genomic DNA library using the polymerase chain reaction. A novel gene, DBIP1, that is closely related to ACBP/DBI but is clearly distinct was identified. DBIP1 bears extensive sequence homology to ACBP/DBI but lacks the introns predicted by rat and duck genomic sequence studies. A 1-base deletion in the coding region results in a frameshift and, along with the absence of introns and the lack of a detectable transcript, suggests that DBIP1 is a pseudogene. ACBP/DBI has previously been mapped to chromosome 2, although this was recently disputed, and a chromosome 6 location was suggested. We show that ACBP/DBI is correctly placed on chromosome 2 and that the gene identified on chromosome 6 is DBIP1.

Amino Acid Sequence↗
PubMed1991

Molecular and endocrine characterization of a mutation involving a recombination between the steroid 21-hydroxylase functional gene and pseudogene.

The gene encoding steroid 21-hydroxylase activity, P450c21B, is located in the major histocompatibility complex (MHC) class III region, in close proximity to a highly homologous pseudogene, P450c21A. Recombinations between P450c21B and P450c21A have been shown to result in deficiency of 21-hydroxylase activity, the usual cause of congenital adrenal hyperplasia (CAH). A mutant P450c21 gene from a patient with simple virilizing CAH was identified and shown to be consistent with a recombination between P450c21A and P450c21B. Sequence analysis of the mutant gene showed the recombination site to be located between the first exon and the second intron. The mutant gene encodes a leucine instead of the normal proline at codon 31. This mutation resides on a chromosome bearing the HLA-B44 serotype. A comparison of mutations associated with HLA-B44 and that normally found with the HLA-Bw47 serotype suggests that the HLA-B44 mutations are of more ancient origin. The patient's homologous chromosome has a deletion of P450c21B. Endocrinological testing therefore allows for testing of the mutant gene in genetic isolation. Such testing demonstrated that the patient was capable of producing aldosterone and retaining sodium in response to a low-sodium diet, indicating that the mutant gene encodes an enzyme with partial 21-hydroxylase activity.

Adrenal Hyperplasia, Congenital↗
PubMed2005

An adenylyl cyclase pseudogene in Mycobacterium tuberculosis has a functional ortholog in Mycobacterium avium.

A number of genes similar to mammalian Class III nucleotide cyclases are found in mycobacteria, and biochemical characterization of some of these proteins has indicated that they code for adenylyl cyclases, with properties similar to the mammalian enzymes. Our earlier bioinformatic analysis had predicted that the Rv1120c gene in Mycobacterium tuberculosis is a pseudogene, while analysis of the genome of Mycobacterium avium indicated the presence of a functional ortholog. We therefore cloned and expressed Rv1120c and its ortholog from M. avium, Ma1120, in Escherichia coli, and find that while the protein from M. tuberculosis is misfolded and found in inclusion bodies, Ma1120 is expressed to high levels as a functional adenylyl cyclase. Sequence analysis of Ma1120 indicates interesting variations in critical amino acids that are known to be important for catalytic activity. Ma1120 is maximally active in the presence of MnATP as substrate ((app)Km approximately 400 microM), and is inhibited by P-site inhibitors (IC50 of 2',5'-dideoxy-3'-adenosine triphosphate approximately 730 nM) and tyrphostins (IC50 approximately 36 microM) in a manner similar to the mammalian enzymes. This therefore represents the first Class III cyclase biochemically characterized from M. avium, and the absence of a functional ortholog in M. tuberculosis suggests a unique role for this enzyme in M. avium.

Adenylyl Cyclase Inhibitors↗
PubMed2004

Identification of 24 genes and two pseudogenes coding for olfactory receptors in Japanese loach, classified into four subfamilies: a putative evolutionary process for fish olfactory receptor genes by comprehensive phylogenetic analysis.

Twenty-four olfactory receptor (OR) genes and two pseudogenes have been identified in the genome of Japanese loach (Misgurnus anguillicaudatus). The genes were classified into four subfamilies according to the similarity of the amino acid sequences. In each subfamily, members showed high sequence similarity not only to each other but also to orthologues of other fish species. The number of members in each OR subfamily was roughly estimated to be from 3 to 10 by genomic Southern blot analysis. The genes of all four OR subfamilies were shown to express on olfactory neurons of the olfactory epithelium by in situ hybridization analysis. Two major features of fish OR genes were found by comprehensive and comparative analyses on OR genes of Japanese loach and other fish species including catfish, zebrafish and pufferfish. First, the phylogenetic tree comprising of representative subfamily members suggests the existence of several prototype genes common to the genomes of many fish species. Second, when all members of orthologous subfamilies identified in each clade of the tree are integrated, the members of a single species comprise a monophyletic group. This means that 'intraspecies' sequence homology, that is, homology among paralogous genes of the same subfamily in a species, is higher than 'interspecies' homology, that is, homology between orthologous genes of different species. This suggests that the subfamily members of a species have evolved recently. Taken together, fish OR genes have evolved from a limited number of prototype genes common to most fish species, and several genes in a subfamily have diversely evolved in each species from each prototype.

Amino Acid Sequence↗
PubMed2004

Characterization of rat heme oxygenase-3 gene. Implication of processed pseudogenes derived from heme oxygenase-2 gene.

Heme oxygenase (HO) is an enzyme responsible for the physiological degradation of heme to produce iron, CO and biliverdin. The released iron is recycled and represents the major source of this metal in heme homeostasis. A putative role as messenger in a signaling pathway is suggested for CO. Biliverdin, together with bilirubin, may function as an antioxidant. Thus far, three isoforms of HO, HO-1, HO-2 and HO-3 have been described. While HO-1 and HO-2 have been extensively investigated, HO-3 is still an elusive and poorly understood isoform. In this study, we examined the structure of the rat HO-3 gene with genomic PCR. However, we failed to isolate the reported HO-3 gene but, instead, found two HO-3-related genes, tentatively named HO-3a and HO-3b, whose sequences differed slightly from each other. Neither gene had any introns and consisted only of exon 2 through 5 of the HO-2 gene, though their sequences were not completely identical with that of HO-2. A stop codon was introduced within the coding regions of these genes due to frame-shift. The nucleotide sequence of their 5'-upstream region largely agreed with long interspersed nuclear element 3. No HO-3-related mRNAs were amplified by RT-PCR, and no HO-3-related proteins were detected in tissues by Western blot analysis. Our results suggested that there are no functional HO-3 genes in rat and that the HO-3a and HO-3b genes are processed pseudogenes derived from HO-2 transcripts.

5' Flanking Region↗
PubMed2004

Human transcription factor Sp3: genomic structure, identification of a processed pseudogene, and transcript analysis.

The human transcription factor Sp3 has been widely studied at the translational level and has been described as a regulatory factor for a number of genes. Sp3 is currently characterized as a bifunctional transcription factor having the ability to behave as both an activator and/or a repressor in various promoter regions. Previous translational studies have attempted to determine the basis for these diverse functions with mostly contradictory evidence to date. Little data are available, however, concerning genomic structure, full-length cDNA, potential transcript variants, or location of translation initiation sites for the large isoform of the Sp3 gene. In this study, bacterial artificial chromosome (BAC) sequencing, reverse transcription-polymerase chain reaction (RT-PCR), genomic PCR, and database mining indicate that the Sp3 gene encompasses seven exons spanning more than 55 kb of genomic DNA on Chromosome 2. The 5' end of this sequence contains a large CpG island. This work also detected a processed pseudogene, psiSp3, located on Chromosome 13, spanning approximately 4.0 kb. Northern blot analysis detected three predominant transcripts at 4.0, 6.0 and 2.5 kb. Sequence analysis indicated that alternative splicing of exon 3 allows for multiple transcripts of Sp3. Each sequenced transcript possesses three to five potential translation initiation sites. This diversity at the level of gene expression will likely be key to understanding the diverse functions of Sp3.

Alternative Splicing↗
PubMed2004

The evolution of the glandular kallikrein locus: identification of orthologs and pseudogenes in the cotton-top tamarin.

Comparisons of the glandular kallikreins loci in human, mouse and rat revealed remarkable differences. For example, the mouse and the rat lack the genes encoding prostate-specific antigen (PSA) and human glandular kallikrein 2 (hK2). In contrast, the intergenic region between KLK1 and KLK15 is devoid of genes and spans only 1.5 kb in humans, but encompasses 23 KLK1-like genes spanning 290 kb in the mouse. To further elucidate the evolution of glandular kallikrein genes, we investigated the structure and organization of these genes in the cotton-top tamarin (Saguinus oedipus), a New World monkey. We conclude that this species has no PSA gene. Moreover, the ortholog of the hK2 gene is a pseudogene, as it contains several mutations that preclude formation of a functional serine protease. The expression of this gene was probably silenced by a 15-bp deletion observed in an androgen response element in the upstream promoter region. Replacing the deleted base pairs in vitro with nucleotides from the human counterpart dramatically restored the transcriptional activity to a level that even surpassed that of the human ortholog. We also determined the nucleotide sequence of KLK15 and the intergenic region between this gene and KLK1 in the cotton-top tamarin. The region between KLK1 and KLK15 is conserved between the cotton-top tamarin and humans, and there are no signs of the extension seen in the mouse. KLK15 appeared to be functional, thus, we predict that it generates a protease with specificity similar to that of the human ortholog.

5' Untranslated Regions↗
PubMed2005

The mouse Krüppel-like Factor 4 (Klf4) gene: four functional polyadenylation sites which are used in a cell-specific manner as revealed by testicular transcript analysis and multiple processed pseudogenes.

The transcription factor Krüppel-like factor 4 (Klf4) is involved in cell cycle arrest and terminal differentiation of many epithelial cell types. We have recently shown that Northern blot analysis of RNA from adult mouse testis revealed multiple Klf4 transcripts. In order to characterize these transcripts, we tested for alternative splicing events and looked for alternative transcriptional initiation and usage of different polyadenylation signals. We neither obtained evidence for alternative splicing nor found transcripts with novel 5' ends. However, we found striking differences in the 3' ends by RACE-PCR. These differences were, interestingly, due to the usage of four alternatively used polyadenylation signals (PAS). This high number of PAS is found in less than 1% of all genes. We show that testicular Sertoli cells exclusively use the first PAS, which is, notably, not canonical, while haploid germ cells rather use the more 3' located PAS-II-IV. The longer transcripts present in germ cells exhibit highly conserved putative binding motifs for proteins known to be important for translational regulation in germ cells. Moreover, we experimentally confirm an intron which was not described in a previous report on the Klf4 gene structure. Finally, we document six Klf4 pseudogenes most likely formed by L1-mediated retrotransposition, indicating germ line expression of Klf4. In summary, we show that mouse testicular cells make intensive use of alternative polyadenylation of Klf4 mRNA strongly suggesting translational regulation of the Klf4 message in spermatids.

3' Untranslated Regions↗
PubMed2006

Ruminants genome no longer contains Whey Acidic Protein gene but only a pseudogene.

Whey Acidic Protein (WAP) has been identified in the milk of only a few species, including mouse, rat, rabbit, camel, pig, tammar wallaby, brushtail possum, echidna and platypus. Despite intensive studies, it has not yet been found in the milk of Ruminants. We have isolated and characterized genomic WAP clones from ewe, goat and cow, identified their chromosomal localization and examined the expression of the endogenous WAP sequence in the mammary glands of all three species. The WAP sequences were localized on chromosome 4 (4q26) as expected from comparative mapping data. The three ruminant WAP sequences reveal the same deletion of a nucleotide at the end of the first exon when compared with the pig sequence. Due to this frameshift mutation, the putative proteins encoded by these sequences do not harbor the features of a usual WAP protein with two four-disulfide core domains. Moreover, RT-PCR experiments have shown that these sequences are not transcribed and are, thus, pseudogenes. This loss of functionality of the gene in Ruminants raises the question of the biological role of the WAP. Some putative roles previously suggested for WAP are discussed.

Animals↗
PubMed2006

Rare mutations of the PIK3CA gene in malignancies of the hematopoietic system as well as endometrium, ovary, prostate and osteosarcomas, and discovery of a PIK3CA pseudogene.

Lipid kinase PIK3CA mutations have been described in several cancers. They clustered in two 'hot spots' located in helical (exon 9) and kinase (exon 20) domains associated with increased kinase activity strongly suggesting oncogenic potential. Mutational analysis of previously unexamined tumors showed an amino acid change from threonine to alanine (T1025A) in exon 20 in one of 28 endometrial cancer samples and 6 endometrial cell lines. Additionally, a silent polymorphism (T1025T) was found in two of 20 MDS samples, one of 43 NHL samples, two of 40 osteosarcoma samples and Ishikawa. The polymorphism was established by identifying two of 92 normal samples with the same change. No PIK3CA mutations were found in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and non-Hodgkin lymphomas (NHL) as well as in osteosarcomas, prostate and ovarian cancer samples. Additionally, a previously unidentified PIK3CA pseudogene spanning exons 9-13 on chromosome 22 was discovered.

Bone Neoplasms↗
PubMed2005

theta-Defensin pseudogenes in HIV-1-exposed, persistently seronegative female sex-workers from Thailand.

The leukocytes of rhesus monkeys contain cyclic octadecapeptides (theta;-defensins) that can protect cells from infection by HIV-1 in vitro. Although humans express mRNA from one or more theta;-defensin pseudogenes, these transcripts contain a premature stop codon that prevents formation of theta;-defensin peptides. We hypothesized that some highly exposed persistently seronegative (HEPS) individuals might have intact theta;-defensin (DEFT) genes and produce functional theta;-defensins that might account for their resistance to HIV-1 infection. We sequenced DEFT genes from 30 women in Chiang Rai, northern Thailand: 11 HEPS female sex-workers and 19 control women (10 HIV-1 infected and 9 HIV-1 uninfected). We found that theta;-defensin genes from all 11 HEPS women contained the crucial signal sequence stop codon, as did the 19 control women. Synthetic theta;-defensins based on the cDNA sequences to generate a human theta;-defensin (termed retrocyclin-1 and -2) were capable of inhibiting replication of Thai HIV-1 subtype B and CRF01_AE isolates regardless of the coreceptor utilization of the isolates. Although our study indicates that synthetic theta;-defensin peptides are effective in vitro against Thai subtype B and CRF01_AE isolates of HIV-1, the presence of premature stop codons in the DEFT genes of these HEPS women makes it unlikely that endogenous theta;-defensin production accounts for their resistance to HIV-1.

Amino Acid Sequence↗
PubMed2004

The p40* adhesin pseudogene of Mycoplasma bovis.

An analogue of the adhesin gene p40 of Mycoplasma agalactiae was found in Mycoplasma bovis. Nucleotide sequence analysis of the p40* gene in M. bovis revealed the presence of a large deletion involving a frameshift that causes premature truncation of the translated protein, indicating that p40* exists as a pseudogene in M. bovis.

Adhesins, Bacterial↗
PubMed2004

Identification of the mouse H-ficolin gene as a pseudogene and orthology between mouse ficolins A/B and human L-/M-ficolins.

Ficolin is a collagenous lectin which plays a crucial role in innate immunity. Three and two ficolins have been identified in human and mice, respectively. To identify the mouse homologue of human H-ficolin and to elucidate the orthology between mouse ficolins A/B and human L-/M-ficolins, the gene structures were explored. The mouse homologue of the H-ficolin gene was identified as a pseudogene on chromosome 4. The mouse ficolin A gene was located far from the ficolin B gene on chromosome 2, whereas the human L-ficolin and M-ficolin genes were close in the region homologous to the ficolin B locus. Together with the exon-intron structures and the phylogenetic tree, these results suggest that ficolin B is the mouse orthologue of M-ficolin and that the genes encoding serum-type ficolins, ficolin A and L-ficolin, were generated independently from the ficolin B/M-ficolin lineage each in mice and primates.

Amino Acid Sequence↗