Putative Modifier Genes Research Articles

Human TRMU encoding the mitochondrial 5-methylaminomethyl-2-thiouridylate-methyltransferase is a putative nuclear modifier gene for the phenotypic expression of the deafness-associated 12S rRNA mutations

Nuclear modifier genes have been proposed to modulate the phenotypic manifestation of human mitochondrial 12S rRNA A1491G mutation associated with deafness in many families world-wide. Here we identified and characterized the putative nuclear modifier gene TRMU encoding a highly conserved mitochondrial protein related to tRNA modification. A 1937 bp TRMU cDNA has been isolated and the genomic organization of TRMU has been elucidated. The human TRMU gene containing 11 exons encodes a 421 residue protein with a strong homology to the TRMU-like proteins of bacteria and other homologs. TRMU is ubiquitously expressed in various tissues, but abundantly in tissues with high metabolic rates including heart, liver, kidney, and brain. Immunofluorescence analysis of human 143B cells expressing TRMU-GFP fusion protein demonstrated that the human Trmu localizes and functions in mitochondrion. Furthermore, we show that in families with the deafness-associated 12S rRNA A1491G mutation there is highly suggestive linkage and linkage disequilibrium between microsatellite markers adjacent to TRMU and the presence of deafness. These observations suggest that human TRMU may modulate the phenotypic manifestation of the deafness-associated mitochondrial 12S rRNA mutations.

Imaging Genomics and Response to Treatment with Antipsychotics in Schizophrenia

Recent important advancements in genomic research have opened the way to new strategies for public health management. One of these questions pertains to how individual genetic variation may be associated with individual variability in response to drug treatment. The field of pharmacogenetics may have a profound impact on treatment of complex psychiatric disorders like schizophrenia. However, pharmacogenetic studies in schizophrenia have produced conflicting results. The first studies examined potential associations between clinical response and drug receptor genes. Subsequent studies have tried to use more objective phenotypes still in association with drug receptor genes. More recently, other studies have sought the association between putative causative or modifier genes and intermediate phenotypes. Thus, conflicting results may be at least in part explained by variability and choice of the phenotype, by choice of candidate genes, or by the relatively little knowledge about the neurobiology of this disorder. We propose that choosing intermediate phenotypes that allow in vivo measurement of specific neuronal functions may be of great help in reducing several of the potential confounds intrinsic to clinical measurements. Functional neuroimaging is ideally suited to address several of these potential confounds, and it may represent a powerful strategy to investigate the relationship between behavior, brain function, genes, and individual variability in the response to treatment with antipsychotic drugs in schizophrenia. Preliminary evidence with potential susceptilibity genes such as COMT, DISC1, and GRM3 support these assumptions.

Pharmacological induction of redundant genes for a therapy of X-ALD: phenylbutyrate and other compounds.

X-linked adrenoleukodystrophy (X-ALD) is a recessive neurologic disease with an incidence among males of 1/17 000. Since the identification of the X-ALD gene (ABCD1) ten years ago (Mosser et al 1993), no satisfactory therapy has been available. A close homologue (ABCD2) was then cloned and presented as a putative modifier gene that could account for some of the extreme phenotypic variability of X-ALD (Lombard-Platet et al 1996). The inducibility of Abcd2 by the hypolipidemic drug fenofibrate in the liver of rodents (Albet et al 1997), correlated to a partial normalisation of the biochemical phenotype of X-ALD (Netik et al 1999), opened up the way of a pharmacological therapy of X-ALD. The basis of such a therapy and the results obtained chiefly in rodents will be presented in this chapter.

A human mitochondrial GTP binding protein related to tRNA modification may modulate phenotypic expression of the deafness-associated mitochondrial 12S rRNA mutation.

Human mitochondrial 12S rRNA A1555G mutation has been found to be associated with deafness. However, putative nuclear modifier gene(s) has been proposed to regulate the phenotypic expression of this mutation. In yeast cells, mutant alleles of MSS1, encoding a mitochondrial GTP-binding protein, manifest a respiratory-deficient phenotype only when coupled with mitochondrial 15S rRNA P(R)(454) mutation corresponding to human A1555G mutation. This suggests that an MSS1-like modifier gene may influence the phenotypic expression of the A1555G mutation. We report here the identification and characterization of human MSS1 homolog, GTPBP3, the first identified vertebrate gene related to mitochondrial tRNA modification. The Gtpbp3 is the mitochondrial GTPase evolutionarily conserved from bacteria to mammals. Functional conservation of this protein is supported by the observation that isolated human GTPBP3 cDNA can complement the respiratory-deficient phenotype of yeast mss1 cells carrying P(R)(454) mutation. GTPBP3 is ubiquitously expressed in various tissues as multiple transcripts, but with a markedly elevated expression in tissues of high metabolic rates. We showed that Gtpbp3 localizes in mitochondrion. These observations suggest that the human GTPBP3 is a structural and functional homolog of yeast MSS1. Thus, allelic variants in GTPBP3 could, if they exist, modulate the phenotypic manifestation of human mitochondrial A1555G mutation.

Isolation and Characterization of the Putative Nuclear Modifier Gene MTO1 Involved in the Pathogenesis of Deafness-associated Mitochondrial 12 S rRNA A1555G Mutation

The human mitochondrial 12 S rRNA A1555G mutation has been found to be associated with aminoglycoside-induced and non-syndromic deafness. However, putative nuclear modifier gene(s) have been proposed to regulate the phenotypic expression of this mutation. In yeast, the mutant alleles of MTO1, encoding a mitochondrial protein, manifest respiratory-deficient phenotype only when coupled with the mitochondrial 15 S rRNA P(R)454 mutation corresponding to human A1555G mutation. This suggests that the MTO1-like modifier gene may influence the phenotypic expression of human A1555G mutation. Here we report the identification of full-length cDNA and elucidation of genomic organization of the human MTO1 homolog. Human Mto1 is an evolutionarily conserved protein that implicates a role in the mitochondrial tRNA modification. Functional conservation of this protein is supported by the observation that isolated human MTO1 cDNA can complement the respiratory deficient phenotype of yeast mto1 cells carrying P(R)454 mutation. MTO1 is ubiquitously expressed in various tissues, but with a markedly elevated expression in tissues of high metabolic rates including cochlea. These observations suggest that human MTO1 is a structural and functional homolog of yeast MTO1. Thus, it may play an important role in the pathogenesis of deafness-associated A1555G mutation in 12 S rRNA gene or mutations in tRNA genes.

A sequence motif found in aDrosophilaheterochromatin protein is conserved in animals and plants

Modifiers of position-effect-variegation in Drosophila encode proteins that are thought to modify chromatin, rendering it heritably changed in its expressibility. In an attempt to identify similar modifier genes in other species we have utilized a known sequence homology, termed chromo box, between a suppressor of position-effect-variegation, Heterochromatin protein 1 (HP1), and a repressor of homeotic genes, Polycomb (Pc). A PCR generated probe encompassing the HP1 chromo box was used to clone full-length murine cDNAs that contain conserved chromo box motifs. Sequence comparisons, in situ hybridization experiments, and RNA Northern blot analysis suggest that the murine and human sequences presented in this report are homologues of the Drosophila HP1 gene. Chromo box sequences can also be detected in other animal species, and in plants, predicting a strongly conserved structural role for the peptide encoded by this sequence. We propose that epigenetic (yet heritable) changes in gene expressibility, characteristic of chromosomal imprinting phenomena, can largely be explained by the action of such modifier genes. The evolutionary conservation of the chromo box motif now enables the isolation and study of putative modifier genes in those animal and plant species where chromosomal imprinting has been described.

The cuticle proteins of Drosophila melanogaster: genetic localization of a second cluster of third-instar genes.

Five third-instar larval cuticle protein genes are placed on the left arm of the third chromosome. For these five genes, 12 variants and two induced mutants are described. All the naturally occurring variants are codominant. One EMS-induced mutant is characterized by the codominant appearance of a new protein, and a second by a recessive mutation that codes for a modifier of third-instar larval cuticle protein 5 (L3CP-5). All but the putative modifier gene map to within less than 0.3 map units of each other on the left arm of the third chromosome at approximately 11. We propose that these genes constitute a cluster of third-instar cuticle protein genes. The induced recessive mutant maps outside of the cluster to a region also on the left arm of the third chromosome. The proteins and their genes should prove useful for both developmental and evolutionary studies.