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PubMed1998

Molecular basis of hereditary C1q deficiency.

Complete selective deficiencies of the complement component C1q are rare genetic disorders which are associated with recurrent infections and a high prevalence of lupus erythematosus-like symptoms. The improvements in molecular biology techniques have facilitated the analysis of such genetic defects to a great extend. To date the basis of C1q deficiencies from 13 families have been studied at the genetic level. In each case single base mutations leading to either termination codons, frame shift or amino acid exchanges were thought to be responsible for these defects as no other aberrations were found. In addition to DNA analysis, conventional immunochemical and biochemical methods have contributed substantially to the elucidation of the structural and functional requirements of this complex macromolecule. The present article reviews the different types of C1q defects in regard to structure and function whereas a detailed presentation on the clinical aspects of C1q deficiencies will be given in this issue of the Journal (by WALPORT, DAVIES and BOTTO).

Amino Acid Substitution↗

PubMed1999

Epidermolysis bullosa simplex associated with muscular dystrophy: phenotype-genotype correlations and review of the literature.

BACKGROUND: Epidermolysis bullosa simplex associated with muscular dystrophy (EBS-MD; OMIM# 226670) is an autosomal recessive disorder caused by genetic defects in the plectin gene. Because EBS-MD is relatively rare, and gene defects have been elucidated only in a limited number of patients, the precise phenotype-genotype correlations have not yet been fully elucidated. OBJECTIVE: The purpose of this study was to define clinical features of EBS-MD and to clarify its phenotype-genotype correlations. METHODS: Clinical, ultrastructural, immunohistochemical, and molecular features of 4 unrelated Japanese patients with EBS-MD were recorded. In addition, 6 cases with defined plectin gene mutations reported in the literature were reviewed. RESULTS: In skin of the EBS-MD patients, the blister formation always occurs just above the hemidesmosomes, and expression of plectin is absent or markedly reduced in all cases examined. All 10 patients, including 6 cases in the literature, showed generalized blistering at birth or soon thereafter, and experienced nail deformities. In addition, decayed teeth (5 cases), urethral strictures (3), mild palmoplantar hyperkeratosis (2), infantile respiratory complications (2), alopecia (1), and laryngeal webs (1) were present. All 8 patients who were older than 9 years demonstrated considerable muscle weakness, and the majority of them ended up being wheelchair bound. Among the 10 patients, 7 were products of consanguineous marriage, 9 have premature termination codon (PTC) mutations in both alleles of the plectin gene, and 7 cases were homozygous for the mutation. One patient who is homozygous for a 2719del9 in-frame deletion mutation that resulted in elimination of 3 amino acids, QEA, could still walk at the age of 46 and showed milder clinical severity. CONCLUSION: EBS-MD reveals clinical features not only characteristic of EBS and MD, but also other manifestations including urethral, dental, and respiratory complications. The majority of patients are products of consanguineous marriage and have homozygous plectin gene mutations. Whereas patients with PTC mutations in both alleles typically showed severe clinical features of EBS-MD and ended up being wheelchair bound, a homozygous patient for an in-frame deletion mutation showed positive, yet attenuated, plectin expression and milder clinical phenotype. Thus plectin immunofluorescence, combined with identification of the underlying plectin mutations, is of value in predicting the severity of the muscle involvement that occurs later in life of patients with EBS-MD.

Child↗

PubMed2001

Genetic susceptibility to multiple sclerosis: detection of polymorphic nucleotides and an intron in the 3' untranslated region of the major histocompatibility complex class II transactivator gene.

The master player in the transcriptional regulation of major histocompatibility (MHC) class II genes is a factor known as the MHC class II transactivator (CIITA). In this study we searched for polymorphisms in the 5' and 3' ends of the human CIITA gene to assess whether or not there is an association between alleles of this gene and multiple sclerosis (MS). Polymorphism screening based upon detection of single strand conformational changes (SSCP analysis) followed by sequencing revealed six single nucleotide variations, namely one in the promoter utilized by B cells and five in the 3' untranslated region (UTR) of the gene. Determination of alleles at these polymorphic sites was facilitated by treatment of amplified DNA fragments with a panel of appropriate restriction enzymes. The distributions of CIITA alleles did not differ between MS patients and control subjects (p > 0.05). After subgrouping of the patients into relapsing-remitting MS and primary progressive MS we found that the distribution of promoter alleles in the latter of these two patient groups differed from that of healthy control subjects (p = 0.04). There was no evidence of linkage disequilibrium between the polymorphic site in the B cell specific promoter and those in the 3' UTR. Based upon the polymorphic sites in the 3' UTR we identified two common CIITA haplotypes which were present at similar frequencies in patients and control subjects. Assuming that susceptibility to MS depends upon type of MHC class II molecule as well as the amounts of expressed class II molecules we tested for interaction between DR15 status and CIITA alleles. No such interaction was detected. Unexpectedly, we identified an intron in the 3' UTR of the human as well as the mouse CIITA gene. Due to the proximity of these introns to the termination codon in both the human and mouse CIITA gene, the mechanism for regulation of transcript stability known as nonsense-mediated decay is probably not involved in the posttranscriptional control of the expression of these genes. So far, the function and significance of the intron in the human and mouse CIITA genes are unknown.

3' Untranslated Regions↗

PubMed1985

Cloning and sequence analysis of the cDNA encoding a snake neurotoxin precursor.

A recombinant plasmid has been constructed containing a sequence of 186 nucleotides encoding a potent neurotoxin found in the venom of the sea-snake Laticauda semifasciata and designated as erabutoxin a. This sequence is flanked, in the upstream region, by a sequence of 60 nucleotides encoding a hydrophobic peptide fragment presumably involved in the secretion process of the neurotoxin. The sequence coding for the toxin ends with a termination codon which is followed by a 3'-untranslated sequence of approximately 240 nucleotides (excluding the poly(A) tract).

Amino Acid Sequence↗

PubMed1985

Computer generation and statistical analysis of a data bank of protein sequences translated from GenBank.

We describe PGtrans, a new and freely available protein sequence databank (2625 sequences, 554198 amino-acids). This data bank is routinely produced by automatic computer translation of the nucleotide sequence library GenBank. The information needed for the translation process (transcriptional orientation, location of coding regions, splice sites and pertinent genetic code) is gathered by the translation program through an "intelligent" scanning of the documentary field of each GenBank entry. Inconsistencies resulting in unexpected termination codons are detected and reported thus allowing the correction of data bank errors. PGtrans is intended as a tool for protein similarity searches. Its reasonable overall size (2 Moctets) makes it suitable for micro-computer environments. Up to date amino-acid composition data and relative abundances of di-, tri-, and tetra-peptides in proteins of known sequences are presented and discussed.

Amino Acid Sequence↗

PubMed2000

Molecular cloning and sequence analysis of the Danio rerio catalase gene.

Catalase is an antioxidant enzyme that plays a central role in the protection against oxidative stress through the metabolism of hydrogen peroxide. Catalase has been well studied in plants, bacteria, and mammals, but little work has been done in other vertebrate species. We have cloned the zebrafish (Danio rerio) catalase cDNA containing the complete coding region and analyzed expression by both reverse transcription polymerase chain reaction and western blot. The deduced amino acid sequence predicts a protein of 526 amino acids with both the primary DNA and amino acid sequences highly conserved among vertebrate species. The major protein-heme contact points in the catalase enzyme complex are also well conserved, although several amino acids associated with the second and third levels of the major substrate channel are not, suggesting potential differences in substrate access or specificity. The 3' flanking region of the cDNA contains a dinucleotide repeat near the termination codon consisting of a near perfect CA array that is polymorphic. The rat and mouse catalase genes also contain a CA repeat sequence in the 3' untranslated region, which, along with an adjacent 5' stem-loop structure, has previously been shown to be a site for mRNA protein binding (Clerch, 1995, Arch. Biochem. Biophys. 317 (1995) 267-274). A stem-loop structure is also predicted adjacent to the zebrafish CA repeat, suggesting a similar role in catalase gene regulation.

Amino Acid Sequence↗

PubMed2000

Gene structure and chromosome mapping of mouse transcription elongation factor S-II (Tcea1).

We report the organization and chromosome localization of the mouse transcription elongation factor S-II gene (Tcea1). This gene was found to be a single copy gene consisting of 10 exons spanning approximately 30kb. Its organization was the same as those of the mouse testis-specific S-II gene (Tcea2) and Xenopus general S-II gene (xTFIIS.oA), but different from that of the human S-II gene family. We also identified a processed pseudogene (Tcea1-ps1) with a sequence highly homologous to those of S-II cDNAs but containing a translation termination codon within its open reading frame. Linkage analysis showed that Tcea1 and Tcea1-ps1 are mapped on mouse chromosomes 1 and 15, respectively. Relationships between Tcea1 and S-II cDNAs isolated so far are discussed.

Animals↗

PubMed2000

Cloning and characterization of the gene encoding mouse IkappaBbeta.

IkappaBbeta is a member of the IkappaB family of structurally related proteins that are important regulators of the inducible transcription factor NF-kappaB. In the present study, the mouse IkappaBbeta gene was cloned and sequenced, and its structure determined. The mouse IkappaBbeta gene contains six exons and five introns that span 7435 nucleotides. A single major transcription initiation site is located 59 nucleotides upstream of the initiating methionine. A translation termination codon and a single polyadenylation signal are found within exon 6. The exon/intron structure of IkappaBbeta and IkappaBalpha genes were compared and found to be very similar, with individual ankyrin repeats being maintained on corresponding exons. This suggests a close evolutionary relationship between these two IkappaB isoforms. The significance of this evolutionary relationship is discussed.

Amino Acid Sequence↗

PubMed2001

Molecular identification of smg-4, required for mRNA surveillance in C. elegans.

Premature termination codons trigger a process in eukaryotes known as nonsense mediated decay or mRNA surveillance, resulting in the rapid decay of the aberrant transcript. Studies in C. elegans have shown this system is mediated by seven smg genes and can prevent the accumulation of toxic, truncated peptides. Here we report the cloning of smg-4 by physical mapping and functional rescue assays. The minimal rescuing activity is found within a genomic operon, encoding a novel protein. The final exon of the gene is alternatively spliced for expression of two different isoforms. Although no known genes were found to exhibit significant homology to smg-4, a novel conserved domain has been identified by alignment with sequences defined by expressed sequence tags (ESTs) from a variety of organisms. Furthermore, we describe a homolog from C. briggsae, which will rescue C. elegans smg-4 mutants. The C. elegans gene has been fused to green fluorescent protein (GFP). This SMG-4:GFP fusion exhibits nuclear accumulation and diffuse cytoplasmic staining, and further localizes to what appear to be perinuclear and cytoplasmic punctate structures.

Alternative Splicing↗

PubMed2002

Striking differences in RNA editing requirements to express the rps4 gene in magnolia and sunflower mitochondria.

The ribosomal protein S4 gene (rps4) has been identified as a single copy sequence in the mitochondrial genomes of two distant higher plants, Magnolia and Helianthus. Sequence analysis revealed that the rps4 genes present in the magnolia and sunflower mitochondrial genomes encode S4 polypeptides of 352 and 331 amino acids, respectively, longer than their counterparts in liverwort and bacteria. Expression of the rps4 genes in the investigated higher plant mitochondria was confirmed by Western blot analysis. In Helianthus, one of two short nucleotide insertions at the 3'-end introduces in the coding region a premature termination codon. Northern hybridizations and reverse transcription-polymerase chain reaction analysis demonstrated that the monocistronic RNA transcripts generated from the rps4 locus in Magnolia and Helianthus mitochondria are modified by RNA editing at 28 and 13 positions, respectively. Although evolutionarily conserved, RNA editing requirements of the rps4 appear more extensive in Magnolia than in Helianthus and in the other higher plants so far investigated. Furthermore, our analysis also suggests that selection of editing sites is RNA sequence-specific in a duplicated sequence context.

Amino Acid Sequence↗

PubMed2002

Genomic structure of the human NLK (nemo-like kinase) gene and analysis of its promoter region.

Recent search revealed that nemo-like kinase (NLK) was identified as a negative regulator of the wingless type signal cascade in Xenopus and in Caenorhabditis elegans. NLK phosphorylates T-cell factor (TCF)/lymphoid enhancer-binding factor (LEF) and interferes with binding of the beta-catenin-TCF/LEF complex to its TCF target site. After we constructed bacterial artificial chromosome clone contig covering more than 45-kb NLK chromosomal gene, genomic cloning revealed that the human NLK gene consists of 11 exons interrupted by ten introns; its translation-initiation site is within exon 1, and the termination codon and polyadenylation signal lie in exon 11. The 289 amino acids of its kinase domain extend from the 3'-portion of exon 1 to the 5'-portion of exon 9, and show a high degree of similarity in amino acid sequence to kinase domains of extracellular-signal regulated kinase 5 (mitogen activated protein kinase 7) and cyclin-dependent kinases, although the positions of introns among those genes are not conserved. Reverse transcription polymerase chain reactions analysis in various tissues showed that NLK is expressed ubiquitously. Analysis of its promoter region by luciferase reporter assays in transfected HeLa and NIH3T3 cells revealed that an upstream region from -487 to +33 bp of the NLK gene contains significant promoter activity. This 5'-flanking region probably contains the cis-acting element of NLK. In addition, our mutation screening showed that NLK was not a mutational target in breast and colorectal tumor cells.

3T3 Cells↗

PubMed2003

Molecular structure and characterization of a novel murine ABC transporter, Abca13.

We report the isolation and structural characterization of the full-length gene and cDNA for a novel mouse ATP-binding cassette (ABC) transporter, Abca13. The mRNA, isolated from mouse kidney, is 6.7 kb in size and encodes a protein consisting of 2143 amino acids with a predicted molecular weight of 240 kDa. The Abca13 gene consists of 44 exons which span 360 kb of genomic sequence. Abca13 has been mapped to mouse chromosome 11.a2, revealing the human orthologue highly conserved on a syntenic region of human chromosome 7p12. The deduced mouse Abca13 protein shows highest amino acid sequence homology to human ABCA1 (50%), ABCA4 (50%), and ABCA12 (56%). Analysis of the putative Abca13 promoter region revealed potential transcription factor binding sites associated with myeloid- and lymphoid-derived cell types. mRNA transcript levels were highest in mouse submaxillary gland, epididymus, ovary, and thymus; with lower levels in a variety of other tissues. An alternative transcript was discovered in mouse kidney devoid of exon 11. The removal of exon 11 by post-transcriptional splicing causes a frameshift in the open reading frame and results in a premature termination codon. We hypothesize that the excision of exon 11 may serve as a regulatory mechanism in kidney, and perhaps other tissues as well. The molecular characterization of the mouse Abca13 gene will establish the foundation for future functional studies of the human ABCA13 transporter.

ATP-Binding Cassette Transporters↗

PubMed1998

Identification of a novel c-DNA overexpressed in Fanconi's anemia fibroblasts partially homologous to a putative L-3-phosphoserine-phosphatase.

We applied the cDNA differential display technique (DDT) in a DNA-repair deficient cell model to isolate genes involved in dysregulation of cell proliferation and development of cancer. The comparative analysis of mRNA expression patterns of human diploid fibroblasts from Fanconi's amemia (FA) and normal phenotype led to the identification of a novel cDNA CO9. Northern blot analysis reveals that CO9 is significantly upregulated in FA fibroblasts but downregulated or absent in fibroblasts from normal donors. CO9 was also highly expressed in FA B-cells of complementation group A and in Raji cells. However, CO9 is not expressed in FA complementation groups B, C, D and E. The full-length cDNA is 840 bp long and contains an open reading frame of 216 bp (72 amino acids), which encodes for a 7.6-kDa protein. The lengths of the 5' and 3' untranslated region are 165 and 459 bp, respectively. The N-terminal and C-terminal nucleotide sequence of CO9 shows homology to a putative human L-3-phosphoserine phosphatase identified recently (HSPSPASE, EMBL Accession No. Y10275) but lacks a 476-bp stretch in the open reading frame. The loss of nucleotides within the open reading frame introduces a new termination codon in the CO9 cDNA along with a novel COOH terminus resulting in a new protein product. Database chromosome mapping localized CO9 to chromosome 7q 11.2. We hypothesize that CO9 represents a novel protein being a partial homologue to the L-3-phosphoserine phosphatase but with a different regulatory cell function.

Amino Acid Sequence↗

PubMed1998

PCR cloning and expression of the molt-inhibiting hormone gene for the crab (Charybdis feriatus).

A PCR-based genomic DNA walking technique was used to clone the gene for the molt-inhibiting hormone of the crab, Charybdis feriatus. Several overlapping genomic clones were isolated, and the MIH gene for the crab was reconstructed. DNA sequence determination of the overlapping clone reveals that the MIH gene spans 4.3kb and consists of three exons and two introns. Exons 1 and 2 carry a coding sequence for the signal peptide, and exons 2 and 3 consist of coding sequence for the mature peptide. The exon-intron boundary of the crab MIH gene also follows the 'GT-AG rule' for the splice donor and acceptor. The deduced amino acid sequence of MIH shows the highest overall similarity to those of the crabs, Callinectes sapidus and Carcinus maenas, and the gonad-inhibiting hormone (GIH) of the lobster. The putative polyadenylation signal is approximately 1.0kb 3' downstream of the termination codon (TGA). Genomic Southern blot analysis indicates that few genomic fragments were hybridized to the cDNA probe. The 5' flanking region contains a putative promoter with several putative cis elements similar to some vertebrate neuropeptide genes. The 530-bp flanking region was subcloned separately to two promoterless reporter plasmids carrying either the Green Fluorescent Protein gene (GFP) or the Choramphenicol Acetyltransferase gene (CAT). The DNA constructs were transfected into insect cells (Sf21) and mouse pituitary cells (GH4ZR7), respectively. Green fluorescent protein was detected in some of the transfected insect cells, and expression of the CAT was detected in cells transfected with DNA constructs containing the crab promoter. By RT-PCR, MIH transcripts can be detected in the eyestalk of shrimp in intermolt, early premolt, late premolt stages and females that brood their eggs. It can also be found in the brain, but not in the ovary, hepatopancreas, muscle and epidermis. During early larval development, MIH mRNA can be detected in the pre-hatched and the newly hatched larvae. Unlike the adult, the expression of the MIH in the larvae is exclusively in the brain.

Amino Acid Sequence↗

PubMed1999

Cloning and characterization of the gene encoding mouse osteoclast differentiation factor.

Osteoclast differentiation factor (ODF), a ligand for osteoclastogenesis inhibitory factor (OCIF)/ osteoprotegerin (OPG), is a member of the membrane-associated tumor necrosis factor (TNF) family and induces osteoclast-like cell formation in vitro. In the present study, mouse ODF genomic clones were isolated and sequenced to determine their gene structure. The mouse ODF gene is a single copy gene consisting of five exons and spans approximately 40kb of the mouse genome. The first exon encodes the intracellular and transmembrane domains. The extracellular region of ODF containing the TNF homologous domain is encoded by exons 1 through 5. The translation-termination codon and six polyadenylation signal residues are present in exon 5. A major transcription-initiation site is present 143 nucleotides upstream of the initiation-ATG codon. This genomic organization is similar to that of other members of the TNF family, especially the CD40 ligand.

Animals↗

PubMed1999

Uridine insertion/deletion RNA editing in trypanosome mitochondria--a review.

The uridine insertion/deletion RNA editing in trypanosome mitochondria is a unique posttranscriptional RNA maturation process that involves the addition or removal of uridine residues at precise sites usually within the coding regions of mitochondrial transcripts. This process creates initiation and termination codons, corrects frameshifts and even builds entire open-reading frames from nonsense sequences. The development of several in-vitro editing assays has provided much insight into the molecular mechanism of RNA editing, which appears to involve cleavage, U addition, exonuclease trimming and ligation, essentially as proposed in the original 'enzyme cascade' model (Blum, B., Bakalara, N., Simpson, L., 1990. A model for RNA editing in kinetoplastid mitochondria: 'Guide' RNA molecules transcribed from maxicircle DNA provide the edited information. Cell 60, 189-198). However, little is known about the biochemical properties of the proteins involved and the significance and role of this process. This article is a review of recent findings on uridine-insertion/deletion editing in trypanosome mitochondria, with an emphasis on the proteins isolated and characterized that may have a role in this process.

Animals↗

PubMed2000

No association found between polymorphisms in genes encoding mGluR7 and mGluR8 and idiopathic generalised epilepsy in a case control study.

The genes of two group III metabotropic glutamate receptors, mGluR7 and 8, are candidate susceptibility genes for epilepsy. The Tyr433Phe polymorphism of mGluR7 and a novel polymorphism in the mGluR8 gene located 29 bp after the termination codon (2756C/T) were investigated in case control association studies performed on DNA from more than 100 patients with idiopathic generalised epilepsy (IGE). No significant association was found with IGE for either polymorphism.

Alleles↗

PubMed2001

Molecular characterization of ionizing radiation-hypersensitive mutant M10 cells.

An ionizing radiation-sensitive mutant derivative of mouse lymphoma L5178Y cell, M10, is defective in rejoining DNA double-strand breaks (DSBs). The complementation test and the results of chromosome transfer suggested that M10 may belong to X-ray cross-complementation (XRCC) group 4. In the present study, sequence analysis of Xrcc4 cDNA in M10 cells disclosed a transversion of A (370) to T, which results in a change of arginine (124) to a termination codon. Interestingly, the mutation occurred in one allele and the transcripts of the Xrcc4 gene were expressed exclusively from the mutant allele. Transfection of M10 cells with the murine Xrcc4 cDNA completely rescued X-ray sensitivity of the mutant cells. M10 is a novel Xrcc4-deficient cell line.

Alleles↗