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PubMed1993

Primary amenorrhoea and infertility due to a mutation in the beta-subunit of follicle-stimulating hormone.

We report a woman with primary amenorrhoea and infertility associated with an isolated deficiency of pituitary follicle-stimulating hormone (FSH), but normal luteinizing hormone (LH) secretion. Ovulation was induced by administration of exogenous FSH and resulted in a successful pregnancy. Sequence analysis of the FSH beta-subunit gene indicated that she is homozygous for a two nucleotide frameshift deletion in the coding sequence. Her mother and son are heterozygous for this mutation. This deletion results in an alteration of amino acid codons 61-86 followed by a premature termination codon. The predicted truncated beta-subunit peptide lacks regions which are important for association with the alpha subunit and for binding to and activation of the FSH receptor. Abnormalities of FSH structure or function might be an under recognised but treatable cause of infertility.

Adult↗
PubMed2001

A nonsense mutation is responsible for the RNA-negative phenotype in human citrullinaemia.

Citrullinaemia is an inborn error of metabolism resulting from a deficiency of argininosuccinate synthetase. Previous studies of RNA of argininosuccinate synthetase of citrullinaemia patients using S1 nuclease analysis have identified a class of so-called RNA-negative alleles in which no stable mRNA can be detected. To investigate the nature of mutation responsible for such a phenotype, a compound heterozygous citrullinaemia carrying an RNA-negative allele and an allele with a 3' splice site mutation in intron 6 (IVS6-2A>G) was analysed. Using sequences of a DNA polymorphism and the IVS6-2A>G mutation as markers, approximately equal amounts of pre-mRNAs from allelic genes were detected suggesting that RNA-negative phenotype could not be the result of defect in transcription initiation. A C-to-T transition converting the CGA arginine codon at residue 279 to a TGA termination codon (R279X) was identified by cDNA sequencing. No accumulation of partially spliced pre-mRNAs containing introns immediately upstream and downstream of the nonsense mutation was observed. In addition, no mRNA species of abnormal size was detected when cDNA from the RNA-negative allele was analysed. Hence, there is no indication of nonsense-associated altered splicing (NAS). The most likely event responsible for the RNA-negative phenotype appears to be nonsense-mediated mRNA decay (NMD).

Alleles↗
PubMed2000

Identification of a founder BRCA2 mutation in Sardinia.

Sardinian population can be instrumental in defining the molecular basis of cancer, using the identity-by-descent method. We selected seven Sardinian breast cancer families originating from the northern-central part of the island with multiple affected members in different generations. We genotyped 106 members of the seven families and 20 control nuclear families with markers flanking BRCA2 locus at 13q12-q13. The detection of a common haplotype shared by four out of seven families (60%) suggests the presence of a founder BRCA2 mutation. Direct sequencing of BRCA2 coding exons of patients carrying the shared haplotype, allowed the identification of a 'frame-shift' mutation at codon 2867 (8765delAG), causing a premature termination-codon. This mutation was found in breast cancer patients as well as one prostate and one bladder cancer patient with shared haplotype. We then investigated the frequency of 8765delAG in the Sardinian breast cancer population by analysing 270 paraffin-embedded normal tissue samples from breast cancer patients. Five patients (1.7%) were found to be positive for the 8765delAG mutation. Discovery of a founder mutation in Sardinia through the identity-by-descent method demonstrates that this approach can be applied successfully to find mutations either for breast cancer or for other types of tumours.

BRCA2 Protein↗
PubMed1986

Murine myb protooncogene mRNA: cDNA sequence and evidence for 5' heterogeneity.

We have sequenced two overlapping cDNA clones from a murine pro-B cell library to generate a composite sequence that includes 3413 bases of the murine c-myb mRNA. There is a single long open reading frame, beginning at the first base of this sequence, and continuing from the first methionine codon at nucleotide 265 to a TGA termination codon at nucleotide 2173. The predicted murine translation product contains 636 amino acid residues and is about 71 kDa long, which is in good agreement with the 75-kDa molecular size determined for the avian c-myb protein. The murine c-myb protein shows a striking 82% amino acid homology in the region (amino acids 71-444) where it can be compared to the published avian c-myb gene sequence. S1 nuclease protection analysis indicates extreme heterogeneity at the 5' end of steady-state murine c-myb mRNA.

Animals↗
PubMed1986

Truncation of the c-myb gene by a retroviral integration in an interleukin 3-dependent myeloid leukemia cell line.

Among a series of myeloid leukemia cell lines, one (NFS-60) was found to have a rearrangement of the c-myb locus. The rearrangement involved the integration of a retrovirus into the region of the gene corresponding to the sixth exon of the avian c-myb locus. The insertion is associated with the production of a truncated RNA and the introduction of a terminator codon at the juncture of the long terminal repeat and the c-myb locus. The properties of the NSF-60 cells were compared with those of other myeloid cell lines, and the known sequence of differentiation induced by interleukin 3. Similar to other myeloid cell lines, the NFS-60 cells do not terminally differentiate in response to interleukin 3, granulocyte/macrophage, or granulocyte colony-stimulating factor suggesting that the cells are transformed with regard to their ability to differentiate. The NFS-60 cells are totally dependent on interleukin 3 for growth and maintenance of viability in vitro but also proliferate in response to granulocyte colony-stimulating factor. The properties of the cells support the concept that the c-myb protooncogene is involved in the control of normal differentiation of hematopoietic cells.

Animals↗
PubMed1989

An ochre mutation in the vitamin D receptor gene causes hereditary 1,25-dihydroxyvitamin D3-resistant rickets in three families.

Hereditary 1,25-dihydroxyvitamin D3-resistant rickets is a rare autosomal-recessive disease resulting from target-organ resistance to the action of the active hormonal form of vitamin D. Four affected children from three related families with the classical syndrome of hereditary 1,25-dihydroxyvitamin D3-resistant rickets and the absence of detectable binding to the vitamin D receptor (VDR) in cultured fibroblasts or lymphoblasts were examined for genetic abnormalities in the VDR gene. Genomic DNA from Epstein-Barr virus-transformed lymphoblasts of eight family members was isolated and amplified by polymerase chain reaction techniques. Amplified fragments containing the eight structural exons encoding the VDR protein were sequenced. The DNA from all affected children exhibited a single C----A base substitution within exon 7 at nucleotide 970 that resulted in the conversion of the normal codon for tyrosine (TAC) into a premature termination codon (TAA) at amino acid 292. This mutation causes a truncation of the VDR protein thereby deleting a large portion of the steroid hormone binding domain (amino acids 292-424). Although the affected children were all homozygotic for the mutation, the four parents tested all exhibited both wild-type and mutant alleles, indicating a heterozygous state. The functional consequences of this mutation were confirmed after expression of the recreated mutant VDR cDNA in mammalian cells. Recreated mutant receptor exhibited no specific 1,25-[3H]dihydroxyvitamin D3 binding and failed to activate a cotransfected VDR promoter-reporter gene construct. Thus these findings identify an ochre mutation in a human steroid hormone receptor in patients with hereditary 1,25-dihydroxyvitamin D3-resistant rickets.

Amino Acid Sequence↗
PubMed1996

Complete structure of the human alpha-albumin gene, a new member of the serum albumin multigene family.

The nucleotide sequence of the human alpha-albumin gene, including 887 bp of the 5'-flanking region and 1311 bp of the 3-flanking region (24,454 in total), was determined from three overlapping lambda phage clones. The sequence spans 22,256 bp from the cap site to the polyadenylylation site, revealing a gene structure of 15 exons separated by 14 introns. The methionine initiation codon ATG is within exon 1; the termination codon TGA is within exon 14. Exon 15 is entirely untranslated and contains the polyadenylylation signal AATAAA. The deduced polypeptide chain is composed of a 21-amino-acid leader peptide, followed by 578 amino acids of the mature protein. There are seven repetitive DNA elements (Alu and Kpn) in the introns and 3-flanking region. The sizes of the 15 alpha-albumin exons match closely those of the albumin, alpha-fetoprotein, and vitamin D-binding protein genes. The exons are symmetrically placed within the three domains of the individual proteins, and they share a characteristic codon splitting pattern that is conserved among members of the gene family. The results provide strong evidence that alpha-albumin belongs to, and most likely completes with, the serum albumin gene family. Based on structural similarity, alpha-albumin appears to be most closely related to alpha-fetoprotein. The complete structure of this family of four tandemly linked genes provides a well-characterized approximately 200 kb locus in the 4q subcentromeric region of the human genome.

Albumins↗
PubMed1992

A new Tay-Sachs disease B1 allele in exon 7 in two compound heterozygotes each with a second novel mutation.

Three novel Tay--Sachs Disease (TSD) mutations have been identified in two unrelated, non-Jewish compound heterozygous patients. A G772C transversion mutation causing an Asp258His substitution is shared by both patients. The mutant enzyme had been characterized, on the basis of previous kinetic studies (1) as a B1, or alpha-subunit active site mutation. This is the first B1 mutation not found in codon 178 (exon 5). A C508T transition causing an Arg170Trp substitution also occurred in one of the patients. The third mutation is a two base deletion occurring in exon 8 involving the loss of either nts 927-928 or 929-930 in codon 310. The deletion creates an inframe termination codon 35 bases downstream. The Arg170Trp mutation was also detected in a third unrelated TSD patient. In both families this allele was traced to French Canadian ancestors originating in the Estrie region of the province of Quebec. This mutation is the third TSD allele unique to the French Canadian population and the ancestral origins of the carrier parents are distant from the center of diffusion of the more common 7.6 kb deletion mutation which is in the eastern part of the province.

Alleles↗
PubMed1994

Congenital adrenal hyperplasia caused by a novel homozygous frameshift mutation 273 delta AA in type II 3 beta-hydroxysteroid dehydrogenase gene (HSD3B2) in three male patients of Afghan/Pakistani origin.

Classical 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency is an autosomal recessive form of congenital adrenal hyperplasia caused by mutations in the type II 3 beta-HSD (HSD3B2) gene. The sequence of the type II 3 beta-HSD gene was determined by direct sequencing of asymmetric PCR products in three male infants suffering from a severe salt-losing form of 3 beta-HSD deficiency and belonging to three families originating from Afghanistan and Pakistan. The three patients were homozygous for the frameshift mutation 273 delta AA resulting from deletion of two adenosines at codon 273, thus leading to a premature termination codon at position 279. This mutation was detected in the heterozygous state in all the relatives studied. The observation that all three patients share the same haplotype for HSD3B1A, HSD3B1C, HSD3B2A, and the microsatellite marker D1S252 indicates that a founder effect is responsible for the severe form of 3 beta-HSD deficiency found in these three families.

3-Hydroxysteroid Dehydrogenases↗
PubMed1983

A frameshift addition causes silencing of the delta-globin gene in an old world monkey, an anubis (Papio doguera).

A delta-globin gene of an anubis, Papio doguera, was cloned, and the nucleotide sequence of a region of about 2,000 bp including the gene was determined. In comparison with that of pSP3, a delta-globin clone from the gene library of a normal Japanese, the anubis delta-globin gene showed one base addition in the second exon at the codon for amino acid 55, generating a termination codon at the new 59th codon. The other differences found in the region analyzed were not considered to affect expression of the delta-globin gene. Therefore, it was concluded that this frameshift addition was at least one of the causes of silencing of the delta-globin gene in the anubis. In addition, from the sequence divergence in the delta-globin gene, the period of this silencing was estimated to be at most 4 million years, and the divergence of anubis occurred at most 30 million years ago.

Animals↗
PubMed1986

Complete nucleotide sequence of recD, the structural gene for the alpha subunit of Exonuclease V of Escherichia coli.

Intracellular amplification of the Escherichia coli RecB and RecC proteins does not result in an increase in Exonuclease V activity unless the level of a third protein, encoded between the recB and argA genes, is also amplified. Nucleotide sequence analysis of this region reveals a 1,824 nucleotide open reading frame which would encode a protein of 608 amino acids with a calculated molecular weight of 66,973. This is assumed to be the structural gene for the alpha subunit of Exonuclease V, recently designated recD. The proposed initiation codon of the recD gene overlaps the termination codon of the upstream recB gene by one nucleotide, suggesting that these genes may form an operon. The deduced amino acid sequence of the RecD protein contains a region which is homologous to highly conserved sequences in adenine nucleotide binding proteins.

Amino Acid Sequence↗
PubMed1993

RNA editing in plant mitochondria and chloroplasts.

In the mitochondria and chloroplasts of flowering plants (angiosperms), transcripts of protein-coding genes are altered after synthesis so that their final primary nucleotide sequence differs from that of the corresponding DNA sequence. This posttranscriptional mRNA editing consists almost exclusively of C-to-U substitutions. Editing occurs predominantly within coding regions, mostly at isolated C residues, and usually at first or second positions of codons, thereby almost always changing the amino acid from that specified by the unedited codon. Editing may also create initiation and termination codons. The net effect of C-to-U RNA editing in plants is to make proteins encoded by plant organelles more similar in sequence to their nonplant homologs. In a few cases, a strong argument can be made that specific C-to-U editing events are essential for the production of functional plant mitochondrial proteins. Although the phenomenon of RNA editing in plants is now well documented, fundamental questions remain to be answered: What determines the specificity of editing? What is the biochemical mechanism (deamination, base exchange, or nucleotide replacement)? How did the system evolve? RNA editing in plants, as in other organisms, challenges our traditional notions of genetic information transfer.

Amino Acid Sequence↗
PubMed1995

The phosphoglycerate kinase and glyceraldehyde-3-phosphate dehydrogenase genes from the thermophilic archaeon Sulfolobus solfataricus overlap by 8-bp. Isolation, sequencing of the genes and expression in Escherichia coli.

The overlapping genes encoding phosphoglycerate kinase (PGK) and glyceraldehyde-3-phosphate dehydrogenase (GraP-DH) from the hyperthermophilic archaeon Sulfolobus solfataricus have been cloned and sequenced. PCR primers based on highly conserved regions of different PGK sequences were used to isolate an internal region of the pgk gene. This was then used to screen a genomic library to isolate the full length pgk gene. A 2.5-kb BglII fragment of S. solfataricus DNA contained both the pgk gene and the gap gene immediately downstream. Unexpectedly, the pgk and gap genes were found to overlap by 8 bp, with the initiation codon of the gap gene preceding the termination codon of the pgk gene. Evidence that the two genes are co-transcribed was obtained by Northern-blot analysis. The S. solfataricus PGK amino acid sequence shows 43% and 45% identity to the PGK sequences of the Archaea Methanobacterium bryantii and Methanothermus fervidus, respectively. High level expression of the S. solfataricus PGK and GraP-DH in Escherichia coli was achieved, with heat treatment at 80 degrees C proving an effective first step in the purification of these recombinant enzymes from extracts of the E. coli host. Purified recombinant S. solfataricus PGK and GraP-DH showed half lives of 39 min and 17 h, respectively, at 80 degrees C. Unlike bacterial GraP-DH enzymes, S. solfataricus GraP-DH was able to use both NAD+ and NADP+ as cofactors, but exhibited a marked preference for NADP+.

Amino Acid Sequence↗
PubMed1989

New mre genes mreC and mreD, responsible for formation of the rod shape of Escherichia coli cells.

New shape-determining genes in the mre cluster at 71 min on the Escherichia coli chromosome map, named mreC and mreD, were identified by complementation experiments using delta mre-678 mutant cells, which have a 5-kilobase-pair deletion encompassing the mre region, and by DNA sequencing. The delta mre-678 mutant cells required three genes, the previously reported mreB gene and the two new genes, to restore the normal rod shape of the cells and normal sensitivity of growth to mecillinam. The mreC gene is preceded by the mreB gene and by a 65-base-pair spacing sequence containing a palindrome sequence and a possible Shine-Dalgarno sequence. The deduced amino acid sequence of the MreC protein consists of 367 amino acid residues with a molecular weight of 39,530. The initiation codon of the mreD gene overlaps the termination codon of the mreC gene by one nucleotide residue. The deduced amino acid sequence of the MreD protein consists of 162 amino acid residues with a molecular weight of 18,755. In vitro, the coding frames of mreC and mreD produced proteins with Mrs of 40,000 and 15,000, respectively, as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

Amdinocillin↗
PubMed1992

Characterization of apolipoprotein B mRNA editing from rabbit intestine.

Apolipoprotein (apo) B-48 is generated by a unique physiological process. Cytidine 6,666 of the apo B primary transcript is posttranscriptionally converted to a uridine by an RNA editing mechanism that transforms the codon for glutamine 2,153 to a termination codon. The editing reaction can be duplicated in a cell-free extract. In this study, the apo B-48 mRNA editing activity derived from partially purified extracts of rabbit enterocytes was characterized. The optimum conditions for the editing reaction were determined to be a salt concentration of 0.125-0.150 M NaCl or KCl, a pH of 8-8.5, and a temperature of 30 degrees C. The reaction rate was linear up to 45 minutes and was proportional to the editing extract concentration. No metal ion cofactors, DNA or RNA cofactors, or energy requirements were identified. At optimum conditions, the reaction followed Michaelis-Menten kinetics, with a Km of 0.4 nM for the rabbit RNA substrate. In addition, the reaction rate was enhanced by the addition of 25 micrograms/ml heparin or 40% glycerol. The characteristics of the editing reaction suggest that it is catalyzed by a nucleotide sequence-specific cytidine deaminase that is either a single enzyme or a multimeric protein.

Animals↗
PubMed2000

Novel mutations of the cathepsin K gene in patients with pycnodysostosis and their characterization.

Pycnodysostosis is a rare autosomal recessive skeletal dysplasia characterized by short stature, osteosclerosis, acroosteolysis, bone fragility, and skull deformities. Recently, mutations in the gene encoding cathepsin K (CK), a lysosomal cysteine protease localized exclusively in osteoclasts, were found to be responsible for this disease. We analyzed genomic DNA from four unrelated Japanese patients with this disorder and identified three different mutations of their CK genes: a previously reported missense mutation (A277 V), a novel single base deletion mutation (531 del T) causing a frame shift from codon 142 that results in a premature termination codon, and a novel missense mutation (L9P) in the signal peptide region. To investigate whether the L9P mutation disrupts signal peptide function and decreases protein synthesis, mutant and wild-type CK complementary DNAs driven by the cytomegalovirus promoter were transfected into COS-7 cells, and their gene products were detected by immunohistochemistry and Western blotting. Expression of the mutant protein was markedly reduced, suggesting decreased mature CK production in this patient, which may have been due to dysfunction of the signal peptide. These results provide evidence that a structural change in the signal peptide of the CK protein was involved in the pathogenesis of pycnodysostosis.

Adult↗
PubMed1999

A novel mutation of the KAL1 gene in Kallmann syndrome.

Kallmann syndrome is defined by the association of hypogonadotropic hypogonadism and anosmia, for which three modes of transmission have been described: X-linked, autosomal recessive and autosomal dominant. The KAL1 gene, responsible for the X-linked form of the disease, has been isolated and its intron-exon organization determined. We report sequence analysis using PCR-direct sequencing method of the entire coding region and splice site junctions of the KAL1 gene in three males with Kallmann syndrome. We found a novel mutation in one case and no mutation in the other two cases. The mutation consisted of a C to T substitution in exon 1 converting codon 66 (CAG) encoding glutamine into a termination codon (TAG)/(Q66X). As a consequence of this mutation, the function of the KAL1 protein consisting of 680 amino acids was severely truncated so as to be consistent with Kallmann syndrome. As only this patient had unilateral renal hypoplasia among the three cases, this would suggest the existence of KAL1 gene mutation in this abnormality.

Adolescent↗