Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The human CYP2D6 gene codes for the enzyme, debrisoquine 4-hydroxylase, which metabolizes over 25 therapeutically important drugs. The inability to metabolize these drugs, which results in a 'poor metabolizer' (PM) phenotype, can be attributed, in some cases, to the presence of any of three previously described mutations in the CYP2D6 gene. To identify new alleles responsible for the PM phenotype, we have examined the CYP2D6 gene from individuals whose phenotypes were not consistent with their apparent genotypes. DNA sequencing revealed a single base deletion in exon 3, T1795, resulting in a frame shift and generating a stop codon one codon after the deletion. A PCR-based test was designed for this new allele (designated CYP2D6(T)) and 236 unrelated individuals from a lung cancer case control study were tested for the presence of the CYP2D6(T) mutation. Eight unrelated individuals were found to carry the D6(T) allele. Four subjects also carry the non-functional D6(B) allele and the drug metabolism phenotypes of these four D6(B)/D6(T) individuals are consistent with the D6(T) allele being responsible for reduced debrisoquine 4-hydroxylase activity. The frequency of the D6(T) allele among Caucasian controls of the case-control study was 1.8% (4/220 chromosomes).
Hum Mol Genet 1994 Jun
PMID:Identification of a new variant CYP2D6 allele with a single base deletion in exon 3 and its association with the poor metabolizer phenotype. 795 Dec 38

Protocatechuate 3,4-dioxygenase catalyzes the aromatic ring cleavage of 3,4-dihydroxybenzoate by incorporating both atoms of molecular oxygen to yield beta-carboxy-cis,cis-muconate. The structure of this metalloenzyme from Pseudomonas aeruginosa (now reclassified as P. putida) has been refined to an R-factor of 0.172 to 2.15 A resolution. The structure is a highly symmetric (alpha beta Fe3+)12 aggregate with a root-mean-square (r.m.s.) difference of 0.18 A among symmetry-related atoms. The tertiary structure of the two polypeptides (alpha and beta) are highly homologous (r.m.s. difference of 1.05 A over 127 C alpha atoms), suggesting that the ancestral enzyme was originally a homodimer with two active sites. Indeed, a non-functional, vestigial active site retains many of the properties of the functional active site but does not bind iron. The coordination geometry of the non-heme iron catalytic cofactor can best be described as trigonal bipyramidal with Tyr447 (147 beta) and His462 (162 beta) serving as axial ligands, and Tyr408 (108 beta), His460 (160 beta) and Wat837 serving as equitorial ligands. The active site environment has a number of basic residues that may promote binding of the acidic substrate. Within the putative active site cavity which is located between alpha and beta chains, five approximately coplanar solvent molecules suggest a position for the planar substrate Trp449 (149 beta), Ile491 (191 beta), defined by Gly14 (14 alpha) and Pro15 (15 alpha). In this position the guanidino group of Arg457 (157 beta) would be buried by the substrate, suggesting a functional role in catalysis.
J Mol Biol 1994 Dec 16
PMID:Structure of protocatechuate 3,4-dioxygenase from Pseudomonas aeruginosa at 2.15 A resolution. 799 Jan 41

The S10 ribosomal protein gene (rps10), which has not been previously reported in any angiosperm mitochondrial genome, was identified by sequence analysis in the potato mitochondrial DNA. This gene is found downstream of a truncated non-functional apocytochrome b (cob) pseudogene, and is expressed as multiple transcripts ranging in size from 0.8 to 5.0 kb. Southern hybridization analysis indicates that rps10-homologous sequences are not present in the wheat mitochondrial genome. Sequence analysis of a single-copy region of the pea mitochondrial genome located upstream of cox1 [11] shows that a non-functional rps10 pseudogene is present in this species. These results suggest that the functional genes coding for wheat and pea mitochondrial RPS10 polypeptides have been translocated to the nucleus.
Plant Mol Biol 1994 Jul
PMID:A ribosomal protein S10 gene is found in the mitochondrial genome in Solanum tuberosum. 806 25

The A mating factor of Coprinus cinereus determines compatibility in mating by regulating part of a developmental sequence that leads to dikaryon formation. The A genes that trigger development encode two different classes of homeodomain proteins, and for a successful mating, a protein of one class, HD1, must interact with a protein of the other class, HD2. In this report we show that C. cinereus A genes that encode HD2 proteins, a2-1 and b2-1, can elicit A-regulated development in the heterologous host C. bilanatus. Transformation rates were very low, suggesting that the genes were poorly transcribed. The fact that the HD2 genes are functionally expressed implies successful heteromultimeric association of putative DNA-binding proteins coded by the two Coprinus species. This interaction was sufficient to satisfy the need for different A factors in the formation of a fertile C. bilanatus dikaryon, but fertile dikaryons were more readily produced in matings with the a2-1 gene transformants. The C. cinereus A genes, b1-1 and d1-1, which encode HD1 proteins, were either not expressed or their proteins were non-functional in C. bilanatus. These experiments raise some interesting questions regarding HD1-HD2 protein interactions.
Mol Gen Genet 1993 Nov
PMID:Expression of A mating type genes of Coprinus cinereus in a heterologous basidiomycete host. 824 2

The germinating asexual spores (conidia) of Neurospora crassa were employed to study steps in the accumulation of transcripts of groups of mitochondrial genes, including those for peptide subunits of cytochrome c oxidase (CO), ATPase (ATP), and apocytochrome b (COB). Physically clustered groups of genes were expressed as cohorts: transcripts of the ATP8-ATP6-mtATP9-CO2 genes were almost undetectable in the dormant spores, and they accumulated rapidly as a group immediately after spore activation. Transcripts of COB and the adjacent CO1 were abundant in the dormant spores, and the dormant and germinating spores contained size forms of the COB transcripts that were not evident in vegetative cells. Polyribosomes were prepared from mitochondrial lysates, and the polyribosomal RNA was probed to identify the mRNAs of specific genes; in several instances polycistronic mRNAs were present in the polyribosomes as were the smaller end-products of the inferred transcript processing pathways. The expression of the physically dispersed genes for subunit peptides of cytochrome c oxidase appears to be regulated to the level of translation; these transcripts are accumulated in the total mitochondrial RNA with sharply different kinetics, but they appeared in the polyribosomes uniformly, their appearance correlating with the uniform synthesis of the subunit peptides. Transcripts for a previously reported non-functional mitochondrial gene, homologous to the functional nuclear gene for ATPase subunit 9, were found in the germinating spores, but were not detected in vegetative cells. These mtATP9 transcripts were also present in the polyribosomes and were apparently translated into a protein in vivo whose synthesis was insensitive to cycloheximide and detectable with an anti-ATP9 subunit antibody. Transcripts for two nuclear genes for mitochondrially localized proteins, ATP9 and CO5, were accumulated in unison and especially rapidly during spore germination.
J Mol Biol 1994 Jan 21
PMID:Expression of mitochondrial genes in the germinating conidia of Neurospora crassa. 828 26

Alterations in kappa light chain expression were demonstrated to originate from genomic changes in the L-V intron (L-IVS) which changed the splicing pattern of the kappa mRNA. In R15, a mutant of mouse myeloma W3129 which produces no kappa light chain, a 358 bp novel sequence element (R15ns) of unknown origin replaced 19 bases of wild-type L-IVS, both altering the normal splicing pattern and activating a cryptic polyadenylation site. Subclones of R15 which reverted to kappa light chain production contained genomic deletions of R15ns and/or the surrounding intron. These deletions led to partial or full restoration of wild type kappa mRNA levels due to further changes in the pattern of mRNA processing. Two cryptic splice acceptor sites and a polyadenylation signal exist in the L-IVS; a cryptic splice acceptor sequence also exists in V kappa. These cryptic sites can be activated by changing the genomic context. It is thus possible to influence light chain expression without altering either the exon sequences or the known regulatory elements. Alterations in splicing patterns also serve to produce kappa light chains with novel variable region sequences and thereby could contribute to antibody diversity. Surprisingly, in the cell line producing this novel kappa light chain, intact alpha heavy chains were secreted in the absence of an apparent association with light chain. These studies also demonstrate that it is not possible to distinguish functional from non-functional genes solely by sequence analysis and that genes can both be inactivated and activated by changes in intron sequences.
Mol Immunol 1994 Feb
PMID:Intron sequences determine the expression of kappa light chain genes. 830 81

The ADP/ATP translocator mediates adenine nucleotide exchange across the inner mitochondrial membrane. ADP/ATP exchange is essential when yeast are grown on a non-fermentable carbon source such as glycerol, but it is not required for growth on glucose. Failure to grow on glycerol is therefore a phenotypic indicator of protein function, and it has been used here to screen site-directed mutants to identify functionally important amino acids in the yeast adenine nucleotide translocator (AAC2). Single mutations of all four charged amino acids in the transmembrane segments of AAC2 (K38A, R96D, R96H, R96L, R96P, R204L, R294A) resulted in loss of function, as did mutations in the matrix arginine cluster (R252I, R253I, R254I). Seven other residues were mutated without affecting growth on glycerol (C73S, C244S, C271S, K179M, K182I, P247G, W235F). The non-functional mutants have been used to select intragenic suppressors to gain further insight into the structure of this membrane transport protein.
J Mol Biol 1993 Apr 20
PMID:Site-directed mutagenesis of the yeast mitochondrial ADP/ATP translocator. Six arginines and one lysine are essential. 848 99

Pregnancy-specific beta 1-glycoprotein (PSG) transcripts have been identified in a number of placental and non-placental tissues. Using a placental PSG cDNA probe to screen a normal human intestinal cDNA library we have isolated 22 hybridizing clones. These clones could be divided into four groups. Nucleotide sequence analysis showed that one group of clones correspond to functional and another group correspond to non-functional PSG cDNAs. The other two groups are homologous to the nonspecific cross-reacting antigen (NCA) and biliary glycoprotein (BGP), both of which are members of the carcinoembryonic antigen (CEA) family. Thus, PSG, NCA and BGP are co-expressed in normal human intestine. RNA and immunoblot analysis, along with polymerase chain reaction amplification further confirm the expression of PSG in human intestinal tissue.
Mol Cell Biochem 1993 Mar 24
PMID:Pregnancy specific beta 1-glycoprotein in human intestine. 848 56

Use of the nitrate reductase encoding gene (nitA) as selection marker has facilitated the successful nuclear transformation of Volvox carteri. The Volvox nitA gene contains 10 introns. A stable nitA mutation in the Volvox recipient strain 153-81 resides in a G-to-A transition of the first nucleotide in the 5' splice site of nitA intron 2. This mutation resulted in at least three non-functional splice variants, namely: (1) intron 2 was not spliced at all; (2) a cryptic 5' splice site 60 nt upstream or (3) a cryptic 5' splice site 16 nt downstream of the mutation were activated and used for splicing. When we used nitA cDNA (pVcNR13) for transformation of V. carteri 153-81, a low efficiency of about 5 x 10(-5) transformants per reproductive cell was observed. Re-integration of either intron 1 (pVcNR15) or introns 9 and 10 (pVcNR16) in the transforming cDNA increased transformation rates to 5 x 10(-4). In parallel, pVcNR15-transformed Volvox exhibited growth rates that were 100-fold increased over the pVcNR13-transformed alga. This intron-enhancement of nitA gene expression appears to be associated with post-transcriptional processing and 'channelling' of the message. These data suggest an important role of splicing for gene expression in V. carteri.
Plant Mol Biol 1996 Apr
PMID:Expression of the Volvox gene encoding nitrate reductase: mutation-dependent activation of cryptic splice sites and intron-enhanced gene expression from a cDNA. 870 42

The CMT1A-REP repeat on chromosome 17p11.2-12 is proposed to mediate misalignment and meiotic unequal crossover leading to a 1.5 Mb pair duplication associated with Charcot-Marie-Tooth neuropathy type 1A (CMT1A) and a reciprocal deletion associated with hereditary neuropathy with liability to pressure palsies (HNPP). Restriction enzyme endonuclease mapping indicated that the size of the CMT1A-REP repeat is approximately 24 kb and DNA sequence analysis determined that the repeat is flanked by inverted Alu sequences. Full length Alu sequences are present at the centromeric ends of the proximal and distal CMT1A-REP repeats and at the telomeric end of the distal repeat. A truncated Alu sequence is present at the telomeric end of the proximal repeat suggesting that the distal CMT1A-REP repeat is the progenitor copy. The crossover breakpoints for a series of unrelated CMT1A and HNPP patients were mapped using a variant SacI site found only in the proximal CMT1A-REP repeat. Seventy-six percent (66/85) of patients had breakpoints which mapped to a 3.2 kb interval, providing further evidence for a recombinational hotspot within the CMT1A-REP repeat. A mariner-like element was mapped within the CMT1A-REP repeat approximately 700 bp centromeric to the 3.2 kb interval containing the hotspot. Analysis of this sequence suggested that it does not encode a functional transposon. By Northern blot analysis a cloned fragment from the CMT1A-REP repeat containing the mariner-like sequence detected a 2.2 kb transcript only in testis. Two cDNA clones which contain the mariner-like element were isolated from a human testis cDNA library. These clones which are interrupted by Alu and other repeats appear to be non-functional versions of the transposon. The functional relationship of the mariner-like element to the recombinational hotspot remains unknown. The origin of the CMT1A-REP repeat was investigated through an analysis of homologous sequences in non-human primates. Southern blot analysis indicated that the chimpanzee has two copies of a CMT1A-REP-like sequence, whereas gorilla, orangutan, and gibbon have a single copy. A high degree of conservation amongst non-human primates for restriction fragments specific to the human distal CMT1A-REP repeat provides further evidence that the distal repeat is the progenitor copy. The mariner-like sequence was detected in association with the CMT1A-REP sequence in all primates studied suggesting that the mariner-like element was introduced into the progenitor CMT1A-REP sequence prior to emergence of the proximal and distal CMT1A-REP repeats. These observations suggest that CMT1A-REP sequence appeared as a repeat before the divergence of chimpanzee and human, but after gorilla and human around 6 to 7 million years ago.
Hum Mol Genet 1996 Jun
PMID:Primate origin of the CMT1A-REP repeat and analysis of a putative transposon-associated recombinational hotspot. 877 88


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