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Results for “Phenotype modifier”

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PubMed2003

Broad phenotypic spectrum caused by an identical heterozygous CDMP-1 mutation in three unrelated families.

CDMP-1, a cartilage-specific member of the TGFss superfamily of secreted signaling molecules, plays a key role in chondrogenesis, growth and patterning of the developing vertebrate skeleton. Homozygous CDMP-1 mutations cause Hunter-Thompson and Grebe types of acromesomelic chondrodysplasia and DuPan syndrome in humans, as well as brachypodism in mice, while heterozygous mutations cause brachydactyly type C (BDC). We present clinical and radiographic data from three unrelated families in which 12 members share the same heterozygous CDMP-1 mutation, an insertion (insG206), resulting in a frameshift predicted to cause functional haploinsufficiency. Although eight mutation carriers display BDC, four have normal hands and feet, confirming nonpenetrance of BDC with CDMP-1 mutations. In addition, several carriers have other skeletal abnormalities, including severe bilateral vertical talus (in two), developmental hip dysplasia (in one), and short stature (in two, who are otherwise unaffected). Premature vertebral end-plate disease was observed in four mutation carriers and was associated with spondylolysis and spondylolisthesis in three of these. Axial skeletal involvement has not been previously reported in association with CDMP-1 mutations. This finding is consistent with CDMP-1 expression in human hypertrophic chondrocytes, which are present in the ring epiphyses of vertebral end plates. Phenotypic variation in BDC has previously been attributed either to locus heterogeneity or to the varied functional effects of different CDMP-1 mutations. The remarkable range of phenotypes caused by this identical CDMP-1 mutation in these families emphasizes the crucial role of genetic background, stochastic variation and/or environmental factors in modifying the observed phenotype. Our findings illustrate that nonpenetrance for the typical features of BDC can be appreciable and that atypical skeletal features that have been reported in some patients with BDC (i.e., clubfoot, short stature, spondylolysis) may also result from CDMP-1 mutation.

Bone Diseases↗

PubMed2005

Genetic regions that interact with loss- and gain-of-function phenotypes of deltex implicate novel genes in Drosophila Notch signaling.

The Notch signaling pathway is an evolutionarily conserved mechanism that regulates many cell fate decisions. The deltex (dx) gene encodes an E3-ubiquitin ligase that binds to the intracellular domain of the Notch protein and regulates Notch signaling in a positive manner. However, it is still not clear how Dx does this. We generated a transgenic line, GMR-dx, which overexpresses dx in the developing Drosophila eye disc. The GMR-dx line showed a rough-eye phenotype, specific transformation of a photoreceptor cell (R3 to R4), and a rotation defect in the ommatidia. This phenotype was suppressed in combination with a dx loss-of-function mutant, indicating that it was due to a dx gain-of-function. We previously reported that overexpression of Dx results in the stabilization of Notch in late endosomes. Here, we found that three motifs in Dx, a region that binds to Notch, a proline-rich motif and a RING-H2 finger, were required for this stabilization, although the relative activity of these variants in this assay did not always correspond to the severity of the rough-eye phenotype. In an attempt to identify novel genes of the Notch pathway, we tested a large collection of chromosomal deficiencies for the ability to modify the eye phenotypes of the GMR-dx line. Twelve genomic segments that enhanced the rough-eye phenotype of GMR-dx were identified. To evaluate the specificity of these interactions, we then determined whether the deletions also interacted with the wing phenotypes associated with a loss-of-function mutation of dx, dx24. Analyses based on whole-genome information allowed us to conclude that we have identified two novel loci that probably include uncharacterized genes involved in Dx-mediated Notch signaling.

Amino Acid Motifs↗

PubMed2001

Organotypic cocultures with genetically modified mouse fibroblasts as a tool to dissect molecular mechanisms regulating keratinocyte growth and differentiation.

Organotypic cocultures of keratinocytes and fibroblasts generate a normal epidermis irrespective of the species and tissue origin of fibroblasts. The use of mouse fibroblasts and human keratinocytes facilitates the identification of the origin of compounds involved in epidermal tissue reconstitution and growth regulation. Moreover, the functional significance for the keratinocyte phenotype of genetically modified fibroblasts from transgenic or knockout mice, even those exhibiting an embryonic lethal phenotype, can be studied in such heterologous in vitro tissue equivalents. Here we communicate results of such studies revealing the antagonistic function of mouse fibroblasts defective in the AP-1 constituents c-Jun and JunB, respectively, on human keratinocyte growth and differentiation. Furthermore, the hematopoietic growth factor granulocyte macrophage-colony stimulating factor has been identified as a novel regulator of keratinocyte growth and differentiation. As will be reported in detail elsewhere both granulocyte macrophage-colony stimulating factor and keratinocyte growth factor have been identified as major mediators of fibroblast-keratinocyte interactions and their expression is induced via AP-1 by interleukin-1 released by the epithelial cells. Thus, these heterologous cocultures provide a novel promising tool for elucidating molecular mechanisms of epithelial-mesenchymal interactions and their consequences on epithelial cell proliferation and differentiation.

Adult↗

PubMed2004

Mapping a syntenic modifier on mouse chromosome 1 influencing the expressivity of the compact phenotype in the myostatin mutant (MstnCmpt-dl1Abc) compact mouse.

A novel method for mapping a modifier gene that is syntenic to its major gene was used to map a male-sex-limited modifier of the expressivity of the Compact phenotype in the myostatin mutant (Mstn(Cmpt-dl1Abc)) Compact mouse. The modifier was mapped to the general region of D1Mit262, 40 cM distal to Mstn on chromosome 1. Myogenin, a postulated downstream target of myostatin, maps to the same region.

Animals↗

PubMed2001

Phenotypic changes of adrenomedullin receptor components, RAMP2, and CRLR mRNA expression in cultured rat vascular smooth muscle cells.

Adrenomedullin is known to inhibit cell proliferation in cultured rat vascular smooth muscle cells, through a cAMP-dependent process. The calcitonin receptor-like receptor could function as an adrenomedullin receptor when co-expressed with receptor activity-modifying protein 2. To determine whether vascular adrenomedullin receptor components, the calcitonin receptor-like receptor and the receptor activity-modifying protein 2, phenotypically change during in vitro culture conditions, we examined the expression of adrenomedullin receptor components, adrenomedullin-induced cAMP production, and the inhibition of cell proliferation in culture rat vascular smooth muscle cells during serial passages. The results demonstrated that the receptor activity-modifying protein 2 and calcitonin receptor-like receptor mRNAs increased in a passage-dependent manner in rat vascular smooth muscle cells. Furthermore, the responses of both the elevation of cAMP and the inhibition of cell proliferation became larger in vascular smooth muscle cells with an increasing number of passages. The results suggest that the increase in functional AM receptor during phenotypic change may in part contribute to the development of vascular lesions, such as in atherosclerosis.

Adrenomedullin↗

PubMed2000

Quantitative trait loci modulate renal cystic disease severity in the mouse bpk model.

Numerous mouse models of polycystic kidney disease (PKD) have been described in which the mutant phenotypes closely resemble human PKD with regard to morphology, cyst localization, and disease progression. As in human PKD, genetic background affects the disease phenotype in mouse PKD models. Using experimental crosses, these modifying effects can be dissected into discrete genetic factors referred to as quantitative trait loci. The locus for the mouse bpk model was recently mapped to chromosome (Chr) 10. In the course of these studies, marked variability was observed in the renal cystic disease expressed in F2 bpk/bpk homozygotes of a (BALB/c-+/bpk x CAST/Ei)F1 intercross. The current study was undertaken to further characterize the renal cystic disease as quantitative trait in this F2 cohort and to map the genetic modifiers that modulate this phenotype. Whole-genome scans revealed a CAST-derived locus on distal Chr 6, near D6Mit14, that affects renal cystic disease severity. Additional analyses identified loci on Chr 1, Chr 2, and Chr 4, as well as a possible interaction between the Chr 6 locus and a locus on distal Chr 1, near D1Mit17. Interestingly, the gene encoding RGS7, a regulator of G protein signaling that binds to polycystin-1, was mapped to the same Chr 1 interval. It is concluded that the severity of the bpk renal cystic disease phenotype is modulated by multiple loci and possibly by epistatic interaction among them. It is hypothesized that the gene encoding the polycystin-binding partner RGS7 is a candidate for the Chr 1 genetic modifier.

Agammaglobulinaemia Tyrosine Kinase↗

PubMed1983

[Lysogeny and lysogenic conversion in methylotrophic bacteria. II. Lysogenic conversion in facultative methanol-assimilating Acetobacter strains].

The lysogenic state of the methylotrophic strain Acetobacter MB 58/1 is completely demonstrated by curing and lysogenization experiments. During these investigations we found that some phenotypic characteristics are modified by the presence or loss of the prophage MO 1. It could be shown that changes of the serological behaviour, the adsorption of the phages and the sensitivity against oxytetracycline are caused by lysogenic conversion. The phenotypic alterations of the bacterial cells induced by the phage genome are the result of modifications of the lipopolysaccharide structures on the cell surface. In the case of oxytetracycline resistance, interactions between the modified lipopolysaccharide structures and specific transport proteins of the cell membranes must be assumed.

Acetobacter↗

PubMed1980

The use of a clonal assay for cytotoxic T lymphocytes to determine the Ly phenotypes of the cytotoxic precursor and effector cells to alloantigens and trinitrophenyl-modified self antigens.

Considerable controversy has arisen regarding the Ly phenotypes of cytotoxic T lymphocytes (CTL) and their precursors (CLP) to alloantigens and modified-self antigens. Although there is general agreement that all CTL and their pregenitors express the Ly2 alloantigen, the presence of the LY1 alloantigen on either CTL or CLP is debated. Clonal assays for CLP, capable of detecting single CLP in the absence of accessory cells, have recently been developed. This assay system provides a sensitive means of determining the Ly phenotypes of CLP to alloantigens or trinitrophenyl- (TNP) modified self antigens. Lymph node cells from C57BL/6 (Ly-1.2, 2.2, 3.2) or CBA (Ly-1.1, 2.1, 3.2) mice were treated with anti-Ly serum and complement (C), and the frequencies of CLP of the treated populations to alloantigens or TNP-modified self antigens were determined. We found that the number of CLP reactive to alloantigens or TNP-modified self antigens were greatly reduced after treatment with either anti-Ly-1 or anti-Ly-2 serum and C in both C57BL/6 and CBA mice. In other words, the CLP to alloantigens or TNP-modified self antigens in these 2 strains of mice are Ly 1+2+. We also found that the CTL derived from the Ly1+2+ CLP were also Ly1+2+. The significance of this finding with respect to the cytotoxic repertoire for alloantigens and modified self antigens is discussed.

Animals↗

PubMed2005

Modifier genes play a significant role in the phenotypic expression of PKD1.

BACKGROUND: Polycystic kidney disease type 1 (PKD1) is characterized by extreme variation in the severity and progression of renal and extrarenal phenotypes. There are significant familial phenotype differences; but it is not clear if this is due to differences in PKD1 mutations, differences in genetic background, or both. METHODS: A total of 315 affected relatives (83 PKD1 families) without end-stage renal disease (ESRD) were evaluated for disease markers, including renal volume, creatinine clearance, proteinuria, liver cysts, and hypertension. Of these patients, 19% progressed to ESRD within 1 to 10 years after the initial examination. Nested analysis of variance was used to investigate interfamilial and intrafamilial differences in these phenotypes. Heritability analyses were used to estimate the effect of the genetic background on phenotypic variability. The age of onset of ESRD was also analyzed with an additional 389 family members from the same PKD1 families without clinical evaluation but with data on age of onset of ESRD (or age without ESRD). RESULTS: There were significant phenotype differences between patients with the same mutation and different genetic backgrounds. The phenotypic variation between patients with different mutations and different genetic backgrounds was not significantly greater than the variation between patients with the same mutation and different genetic backgrounds. However, when the 389 family members were included, both the mutation and modifier genes had significant effects on the age of onset of ESRD. Inherited differences in genetic background were estimated to account for 18% to 59% of the phenotypic variability in PKD1 disease markers in patients prior to ESRD and in the subsequent progression to ESRD (43% heritability) in the 315 patients who were clinically evaluated. CONCLUSION: Modifier loci in the genetic background are important factors in inter- and intrafamilial variability in the phenotypic expression of PKD1. The extreme intrafamilial phenotype differences are consistent with the hypothesis that one or a few modifier genes have a major effect on the progression and severity of PKD1.

Adult↗

PubMed2006

Genotype-epigenotype-phenotype correlations in females with frontometaphyseal dysplasia.

Frontometaphyseal dysplasia (FMD) belongs to a group of overlapping skeletal dysplasias, the common molecular basis of which are mutations of FLNA, the gene encoding filamin A. The nature of the mutation has been considered the major determinant of the phenotype within this group that comprises the otopalatodigital syndromes (OPD1, OPD2) and Melnick-Needles syndrome besides FMD. However, to date the molecular pathomechanisms are not well understood. In FMD only few FLNA mutations have been reported which do not cluster in a specific region of the protein. We report on a novel de novo mutation 5182G --> T in exon 31 of the FLNA gene in a girl with manifestations of FMD and OPD1. This mutation is predicted to lead to the exchange of a highly conserved glycine residue at position 1,728 by cysteine (G1728C) in repeat 15 of the filamin A rod domain. In a second family with FMD, we identified a known mutation (S1186L) in a mother and her son. In contrast to most previous reports on manifesting females or carriers of the FLNA-related skeletal dysplasias, the affected females presented here showed only mild to moderate skewing of X-inactivation against the mutant allele. Our data may indicate that in females, genotype-phenotype correlation between certain FLNA mutations and OPD1 and FMD, respectively, is less strict than previously assumed. We propose that X-inactivation is an important epigenetic modifier of the phenotype in females with the FLNA-related skeletal dysplasias.

Abnormalities, Multiple↗

PubMed2000

Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes.

We and others have recently identified mutations in the ABCA1 gene as the underlying cause of Tangier disease (TD) and of a dominantly inherited form of familial hypoalphalipoproteinemia (FHA) associated with reduced cholesterol efflux. We have now identified 13 ABCA1 mutations in 11 families (five TD, six FHA) and have examined the phenotypes of 77 individuals heterozygous for mutations in the ABCA1 gene. ABCA1 heterozygotes have decreased HDL cholesterol (HDL-C) and increased triglycerides. Age is an important modifier of the phenotype in heterozygotes, with a higher proportion of heterozygotes aged 30-70 years having HDL-C greater than the fifth percentile for age and sex compared with carriers less than 30 years of age. Levels of cholesterol efflux are highly correlated with HDL-C levels, accounting for 82% of its variation. Each 8% change in ABCA1-mediated efflux is predicted to be associated with a 0.1 mmol/l change in HDL-C. ABCA1 heterozygotes display a greater than threefold increase in the frequency of coronary artery disease (CAD), with earlier onset than unaffected family members. CAD is more frequent in those heterozygotes with lower cholesterol efflux values. These data provide direct evidence that impairment of cholesterol efflux and consequently reverse cholesterol transport is associated with reduced plasma HDL-C levels and increased risk of CAD.

ATP Binding Cassette Transporter 1↗

PubMed1989

Genetic analysis of modifiers affecting sexual dimorphism and temperature sensitivity of bx1 in Drosophila melanogaster.

Two modifiers of bithorax1 phenotypic expression are described. An X-chromosome region is associated with sexual dimorphism in bx1 penetrance. It is hypothesized that sexual dimorphism is in part due to a lack of dosage compensation of the modifier, in males. A third chromosome region that segregates with the pink peach allele is implicated in mediating temperature sensitivity. By appropriate combinations of modifiers, both sexual dimorphism and temperature sensitivity can be greatly reduced.

Alleles↗

PubMed2004

The gar2 and rga alleles increase the growth of gibberellin-deficient pollen tubes in Arabidopsis.

Ectopic expression in Arabidopsis of a pea (Pisum sativum) cDNA (2ox2) encoding a gibberellin (GA) 2-oxidase (PsGA2ox2), involved in the deactivation of biologically active GAs, has been used to establish a role for GAs in promoting pollen tube growth. One line, 35S:2ox2/28c, when homozygous for the transgene, exhibits a novel small fruit phenotype. The 28c transgene reduces pollen tube growth, and this results in a reduced number of fertilized seeds that are only present at the end of the silique nearest the stigma. To confirm that the 28c pollen tube phenotype is due to sense expression of the 2ox2 mRNA, a "hairpin" RNA interface silencing construct, designed to silence 2ox2 expression, has been used to restore pollen tube growth and fruit development. The interaction between 28c and other mutants with increased GA response has also been examined to provide further evidence that GAs play an important role in pollen tube growth. Based on the ability of mutant alleles to suppress the 35S:2ox2/28c phenotype, we define new roles for the gar2-1 and rga alleles in GA signaling during pollen tube elongation in addition to their previously established roles in vegetative tissues. In contrast to the constitutive GA response observed in internodes and leaves lacking RGA and GAI, the rga-2 gai-d5 mutant combination is only a partial suppressor of the 28c phenotype. Because the dominant dwarfing gai-1 allele reduces GA response in vegetative tissues, its effect on plant fertility has been examined. Although gai-1 reduces seed set, this appears to reflect defects in reproductive development other than pollen tube function. Finally, we show that the genetic background (Landsberg erecta or Columbia) modifies the 28c phenotype and that this effect is not due to the ER/er difference between these two ecotypes.

Alleles↗

PubMed1996

Phenotypic variation in Waardenburg syndrome: mutational heterogeneity, modifier genes or polygenic background?

We have identified 11 mutational changes in the PAX3 gene in patients with type 1 Waardenburg syndrome (WS1) including three in the paired domain, six within or immediately adjacent to the homeodomain and two previously described polymorphic variants in exons 2 and 6. The affected members of one family carried substitutions involving two base pairs separated by one unaltered codon. Two of the deleterious mutations were identical and three others were identical to previously reported mutations. A comparison of clinical findings in families carrying substitutions in the same codon failed to reveal conspicuous similarities. Although subtle mutation-specific effects may well exist, allelic heterogeneity clearly cannot account for within family variation. However, the striking concordance of a pair of monozygotic twins with Waardenburg syndrome (WS) and previous reports of similar pairs indicate that phenotypic variation in WS has a genetic basis. If the genetic effects are mediated by oligogenic epistasis, as studies in the mouse suggest, it may ultimately be possible to predict clinically relevant aspects of the Waardenburg phenotype.

Amino Acid Sequence↗

PubMed1997

Diets enriched in docosahexaenoic acid fail to correct progressive rod-cone degeneration (prcd) phenotype.

PURPOSE: Results of a previous study show abnormal plasma lipids in progressive rod-cone degeneration (prcd)-affected dogs, with lower docosahexaenoic acid (DHA; 22:6n-3) and cholesterol levels but no differences in other plasma fatty acids, lipids, triglycerides, and fat-soluble vitamins. There is also an increase of the DHA precursor 22:5n-3, so that the ratio of 22:5n-3 to 22:6n-3 is higher in affected than in normal dogs. Because DHA is the predominant esterified fatty acid in rod outer segment (ROS) phospholipids, these findings suggest a possible causal association between abnormal plasma lipid levels and retinal degeneration. In the current study, dietary supplements rich in 22:6n-3 were used to determine whether plasma, liver, and rod outer segment phospholipid composition can be altered to modify the prcd disease phenotype. METHODS: prcd-affected and normal control dogs were given DHA-enriched supplements for short (7- and 25-day) and long (21-week) periods, and the fatty acid composition of plasma, liver, and rod outer segment phospholipids were examined. In the long-term study, electroretinography and morphology were used to assess modification of the retinal degeneration phenotype. RESULTS: Administration of DHA-enriched supplements resulted in increases in plasma DHA and n-3 polyunsaturated fatty acids and in decreases in some n-6 fatty acids in normal and prcd-affected dogs. Similar increases in DHA and n-3 fatty acids were observed in the liver, but affected dogs had significantly higher levels at all supplementation time points examined. In contrast, the ROS of affected dogs had statistically lower (approximately 20%) DHA levels, and these levels could not be increased with dietary supplementation. The disease phenotype could not be modified by DHA-enriched supplements. CONCLUSIONS: Regardless of the sustained three- to fourfold elevation in plasma and liver DHA that occurs as the result of supplementation, the ROS DHA levels remain unchanged, and the prcd disease phenotype is not modified by the dietary manipulation. These findings could be the result of a reduction in the synthesis of DHA-containing phospholipids in the retinas of affected dogs; or, alternatively, there could be a reduction in DHA uptake, transport, or storage within the retinal pigment epithelium-photoreceptor complex.

Animals↗

PubMed2001

A founder mutation of the potassium channel KCNQ1 in long QT syndrome: implications for estimation of disease prevalence and molecular diagnostics.

OBJECTIVES: We took advantage of the genetic isolate of Finns to characterize a common long QT syndrome (LQTS) mutation, and to estimate the prevalence of LQTS. BACKGROUND: The LQTS is caused by mutations in different ion channel genes, which vary in their molecular nature from family to family. METHODS: The potassium channel gene KCNQ1 was sequenced in two unrelated Finnish patients with Jervell and Lange-Nielsen syndrome (JLNS), followed by genotyping of 114 LQTS probands and their available family members. The functional properties of the mutation were studied using a whole-cell patch-damp technique. RESULTS: We identified a novel missense mutation (G589D or KCNQ1-Fin) in the C-terminus of the KCNQ1 subunit. The voltage threshold of activation for the KCNQ1-Fin channel was markedly increased compared to the wild-type channel. This mutation was present in homozygous form in two siblings with JLNS, and in heterozygous form in 34 of 114 probands with Romano-Ward syndrome (RWS) and 282 family members. The mean (+/- SD) rate-corrected QT intervals of the heterozygous subjects (n = 316) and noncarriers (n = 423) were 460 +/- 40 ms and 410 +/- 20 ms (p < 0.001), respectively. CONCLUSIONS: A single missense mutation of the KCNQ1 gene accounts for 30% of Finnish cases with LQTS, and it may be associated with both the RWS and JLNS phenotypes of the syndrome. The relative enrichment of this mutation most likely represents a founder gene effect. These circumstances provide an excellent opportunity to examine how genetic and nongenetic factors modify the LQTS phenotype.

Adolescent↗

PubMed1986

Debrisoquine oxidation in an Australian population.

The standard laboratory method for determination of debrisoquine phenotype has been modified and shortened with no loss of sensitivity. Debrisoquine metabolic ratios (MR) at 4 and 8 h showed excellent correlation indicating that collection time can also be shortened. Same day phenotyping is therefore possible. One hundred normal, Caucasian Australian subjects were phenotyped (46 males, 54 females) and 6% were poor metabolisers (PM) of debrisoquine. Fifty of the original subjects were also acetylation phenotyped and 34% were fast and 66% slow acetylators. One PM of debrisoquine was a fast acetylator of sulphadimidine and four PM were slow acetylators. This was a non-significant association.

Acetylation↗

PubMed2002

Arylamine N-acetyltransferase type 2 and glutathione S-transferases M1 and T1 polymorphisms in familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) exhibits a variable phenotype even in carriers of the same adenomatous polyposis coli germline mutation. Xenobiotic-metabolizing enzymes such as N-acetyltransferases (NATs) and glutathione S-transferases (GSTs) were reported to modify the individual risk for colorectal cancer. We examined whether the polymorphisms of the NAT2, GSTM1, and GSTT1 enzymes affect age at diagnosis of first colorectal adenomas or extracolonic manifestations in 411 FAP patients. Neither age at diagnosis of colorectal adenomas nor occurrence of extra-intestinal tumors differed significantly between genotypes at the NAT2 and GSTM1 loci, whereas GSTT1 polymorphism showed an uncertain association with extra-intestinal manifestations. Combinations of supposed at risk genotypes of the three enzymes showed no significant differences either. Thus, NAT2, GSTM1, or GSTT1 are unlikely to modify the disease phenotype in FAP patients.

Adenomatous Polyposis Coli↗