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Results for “Phenotype modifier”

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PubMed2003

Mapping modifiers affecting muscularity of the myostatin mutant (Mstn(Cmpt-dl1Abc)) compact mouse.

The hypermuscular Compact phenotype was first noted in a line of mice selected for high body weight and protein content. A new line, based on mice showing the Compact phenotype, was formed and selected for maximum expression of the Compact phenotype. Previously we mapped and identified a 12-bp deletion in the myostatin gene, denoted Mstn(Cmpt-dl1Abc), which can be considered as a major gene responsible for the hypermuscular phenotype. Genetic analysis revealed that full expression of the hypermuscular phenotype requires the action of modifier loci in addition to Mstn(Cmpt-dl1Abc). To map these modifier loci, an interspecific F(2) population was generated between Comp9, an inbred line homozygous for Mstn(Cmpt-dl1Abc), and CAST/Ei, an inbred line generated from Mus musculus castaneus. Selective DNA pooling and genotyping, separately by gender, was carried out within a subpopulation of the F(2) consisting of individuals homozygous for Mstn(Cmpt-dl1Abc). Significant association with hypermuscularity at a false discovery rate (FDR) of 0.05 was found for markers on chromosomes 3, 5, 7, 11, 16, and X. In all cases, the marker allele derived from the Comp9 parent showed a higher frequency in the hypermuscular group and the CAST/Ei allele in the normal group. The modifier loci apparently exerted their effects on muscularity only in the presence of Mstn(Cmpt-dl1Abc).

Animals↗

PubMed1994

The rolB Gene of Agrobacterium rhizogenes Does Not Increase the Auxin Sensitivity of Tobacco Protoplasts by Modifying the Intracellular Auxin Concentration.

Phenotypical alterations observed in rolB-transformed plants have been proposed to result from a rise in intracellular free auxin due to a RolB-catalyzed hydrolysis of auxin conjugates(J.J. Estruch, J. Schell, A. Spena [1991] EMBO J 10: 3125-3128).We have investigated this hypothesis in detail using tobacco (Nicotiana tabacum) mesophyll protoplasts isolated from plants transformed with the rolB gene under the control of its own promoter (BBGUS 6 clone) or the cauliflower mosaic virus 35S promoter (CaMVBT 3 clone). Protoplasts expressing rolB showed an increased sensitivity to the auxin-induced hyperpolarization of the plasma membrane when triggered with exogenous auxin. Because this phenotypical trait was homogeneously displayed over the entire population, protoplasts were judged to be a more reliable test system than the tissue fragments used in previous studies to monitor rolB gene effects on cellular auxin levels. Accumulation of free 1-[3H]-naphthaleneacetic acid (NAA) was equivalent in CaMVBT 3, BBGUS 6, and wild-type protoplasts, Naphthyl-[beta]-glucose ester, the major NAA metabolite in protoplasts, reached similar levels in CaMVBT 3 protoplasts, reached similar levels in CaMVBT 3 and normal protoplasts and was hydrolyzed at the same rate in BBGUS 6 and normal protoplasts. Furthermore, NAA accumulation and metabolism in BBGUS 6 protoplasts were independent of the rolB gene expression level. Essentially similar results were obtained with indoleacetic acid. Thus, it was concluded that the rolB-dependent behavior of transgenic tobacco protoplasts is not a consequence of modifying the intracellular auxin concentration but likely results from changes in the auxin perception pathway.

Journal Article↗

PubMed2005

Decreased expression of ABCD4 and BG1 genes early in the pathogenesis of X-linked adrenoleukodystrophy.

Childhood cerebral adrenoleukodystrophy (CCER), adrenomyeloneuropathy (AMN) and AMN with cerebral demyelination (AMN-C) are the main phenotypic variants of X-linked adrenoleukodystrophy (ALD). It is caused by mutations in the ABCD1 gene encoding a half-size peroxisomal transporter that has to dimerize to become functional. The biochemical hallmark of ALD is the accumulation of very-long-chain fatty acids (VLCFA) in plasma and tissues. However, there is no correlation between the ALD phenotype and the ABCD1 gene mutations or the accumulation of VLCFA in plasma and fibroblast from ALD patients. The absence of genotype-phenotype correlation suggests the existence of modifier genes. To elucidate the mechanisms underlying the phenotypic variability of ALD, we studied the expression of ABCD1, three other peroxisomal transporter genes of the same family (ABCD2, ABCD3 and ABCD4) and two VLCFA synthetase genes (VLCS and BG1) involved in VLCFA metabolism, as well as the VLCFA concentrations in the normal white matter (WM) from ALD patients with CCER, AMN-C and AMN phenotypes. This study shows that: (1) ABCD1 gene mutations leading to truncated ALD protein are unlikely to cause variation in the ALD phenotype; (2) accumulation of saturated VLCFA in normal-appearing WM correlates with ALD phenotype and (3) expression of the ABCD4 and BG1, but not of the ABCD2, ABCD3 and VLCS genes, tends to be correlated with the severity of the disease, acting early in the pathogenesis of ALD.

ATP-Binding Cassette Transporters↗

PubMed2002

Characterization of a major modifier locus for polycystic kidney disease (Modpkdr1) in the Han:SPRD(cy/+) rat in a region conserved with a mouse modifier locus for Alport syndrome.

The genetic analysis of rodent disease models provides a powerful tool to investigate how modifier loci cause variation in the phenotypic expression of a disease. In order to test the existence of modifier loci influencing polycystic kidney disease (PKD) phenotypes, we derived a backcross between PKD susceptible Han:SPRD(cy/+) and control Brown Norway (BN) rats, and performed a whole-genome scan in 182 PKD affected hybrids showing different grades of disease severity. The genetic dissection of PKD in the cross allowed us to detect a modifier locus, Modpkdr1, on rat chromosome 8 that controls PKD severity, kidney mass and plasma urea concentration. Results from database searches and computational analyses demonstrated that the Modpkdr1 locus shows strong evidence of synteny conservation with human and mouse chromosomal regions controlling kidney diseases, including disease progression of Alport syndrome. Comparative genome mapping also provided an inventory of potential candidate genes for modifier(s) of PKD. Analyses of the coding regions for four strong candidates (Ctsh, Bcl2a1, Trpc1 and Slc21a2) in (cy/+), BN and Lewis rat strains did not reveal sequence variants that could be associated with PKD. The characterization of Modpkdr1 may provide new insights into modulating mechanisms involved in the pathogenesis of PKD that could delay disease progression in humans. It may also have strong implications in the identification of pathophysiological factors common to different renal disorders.

Animals↗

PubMed2006

The role of mutagenesis in defining genes in behaviour.

The study of human behavioural and psychiatric disorders benefits from the development of genetic models in mice and other organisms. Mouse mutants allow one to investigate the molecular basis of disease progression and to develop novel therapies. The number of potential mouse models is increasing dramatically through the implementation of mutagenesis screens for aberrant behavioural phenotypes. The alkylating agent N-ethyl-N-nitrosourea ENU is the mutagen of choice in these screens as it induces mutations at a very high rate. Progeny of chemically-mutagenised animals are screened either in systematic high-throughput test batteries or in specific low-throughput tests. Both approaches have been highly successful with large numbers of novel loci being identified and characterised. Many mutant lines are available for general research with phenotypes and genetic map positions on public websites. Of the mutant genes characterised, the majority have contributed to our knowledge of gene function in physiology and disease. The 'mutagenesis screening' approach continues to evolve through the design of new phenotyping strategies. The development of modifier screens in mice shows promise in the elucidation of complex phenotypes whereas the use of mutagenesis in combination with pharmacological agents targets specific neurochemical systems. Finally, the systematic screening approach has demonstrated that mutations are likely to affect more than one biological process.

Alkylating Agents↗

PubMed1990

[Immunophenotypic analysis of human endothelial cells].

Very Little is known about the immunological attributes of human endothelial cells. In this study, we performed immunologic phenotypic analysis of cultured human dermal microvascular endothelial cells in comparison with human umbilical vein endothelial cells and examined the ability of various biologic response modifiers to alter the phenotypes. Using FACS analysis, both types of the cells appear to lack many of the cell surface markers of immunologically proficient cells, E.G. OKT4, OKT8, Leu7, FcIgG receptor, complement receptors, IL-2 receptor and HLA-Dr, but they possess beta 2-microglobulin and DAF. HLA-Dr antigens can be induced on both types of endothelial cells by gamma-IFN in a dose and time dependent manner. Both types of endothelial cells possess several kinds of Cell Adhesion Molecules (CAMs), such as ICAM-1, CD44, LFA-3, but not LFA-1 or CD2. ICAM-1 but not LFA-3 or CD44 can be upregulated by exposure of both types of endothelial cells to gamma-IFN, IL-1 and TNF. These data suggest that endothelial cells of the dermal microvasculature may play central roles in a variety of different cutaneous inflammation.

Antigens, Surface↗

PubMed2001

CYCLIN D1 as a genetic modifier in hereditary nonpolyposis colorectal cancer.

Hereditary nonpolyposis colorectal cancer is associated with inherited defects in DNA mismatch repair. Clinical variation even in cases with identical predisposing mutations suggests the existence of other factors contributing to the phenotype. We addressed the modifying role of the common A/G polymorphism in exon 4 and the alternatively spliced transcripts a and b of the CCND1 gene encoding cyclin D1 in a series of 146 affected carriers of 10 MLH1 and 3 MSH2 mutations. No correlation was observed between a particular allele (A versus G) and age at onset. However, the presence of the variant transcript b in blood/normal mucosa, by multiplex reverse transcription-PCR, was associated with a significantly lower age at onset of colon cancer as compared with individuals with transcript a only (35 versus 46 years; P = 0.02). Whereas our data do not support a modifying role of A versus G allele of CCND1, the results do suggest that the relative abundance of a and b transcripts may modify the age at onset of colon cancer in hereditary nonpolyposis colorectal cancer.

Adaptor Proteins, Signal Transducing↗

PubMed1993

Down-modulation of epidermal growth factor receptor accompanies TNF-induced differentiation of the DiFi human adenocarcinoma cell line toward a goblet-like phenotype.

Although the biologic response modifier tumor necrosis factor-alpha (TNF) is a known differentiation inducer in hematopoietic cells, its role in differentiation of other tissue types has yet to be elucidated. In the studies presented here, TNF treatment of the human rectal adenocarcinoma cell line, DiFi, elicits characteristics of early stage differentiating, mucin-producing colonocytes. Not only are TNF-treated DiFi cells growth-inhibited by TNF, but they also display a unique morphology. Additionally, TNF treatment of DiFi cells enhances > fivefold the expression of high molecular weight mucin glycoproteins, as measured by [125I]-wheat germ agglutinin (WGA) binding and the human milk fat globule-1 (HMFG-1) anti-MUC1 antibody reactivity. The induction of these differentiation characteristics correlates with novel alterations in epidermal growth factor receptor (EGF-R). Following 5-day TNF treatment of DiFi cultures, EGF receptor levels, kinase autophosphorylation activity, and receptor tyrosine phosphorylation are reduced by > fourfold. The establishment of a model system in which goblet-like cell characteristics and alterations in a growth factor receptor can be induced in vitro may be potentially useful in studying the underlying mechanisms of colonic epithelial cell proliferation and differentiation.

Adenocarcinoma↗

PubMed2005

Genetic interaction of Lobe with its modifiers in dorsoventral patterning and growth of the Drosophila eye.

Dorsoventral (DV) patterning is essential for growth of the Drosophila eye. Recent studies suggest that ventral is the default state of the early eye, which depends on Lobe (L) function, and that the dorsal fate is established later by the expression of the dorsal selector gene pannier (pnr). However, the mechanisms of regulatory interactions between L and dorsal genes are not well understood. For studying the mechanisms of DV patterning in the early eye disc, we performed a dominant modifier screen to identify additional genes that interact with L. The criterion of the dominant interaction was either enhancement or suppression of the L ventral eye loss phenotype. We identified 48 modifiers that correspond to 16 genes, which include fringe (fng), a gene involved in ventral eye patterning, and members of both Hedgehog (Hh) and Decapentaplegic (Dpp) signaling pathways, which promote L function in the ventral eye. Interestingly, 29% of the modifiers (6 enhancers and 9 suppressors) identified either are known to interact genetically with pnr or are members of the Wingless (Wg) pathway, which acts downstream from pnr. The detailed analysis of genetic interactions revealed that pnr and L mutually antagonize each other during second instar of larval development to restrict their functional domains in the eye. This time window coincides with the emergence of pnr expression in the eye. Our results suggest that L function is regulated by multiple signaling pathways and that the mutual antagonism between L and dorsal genes is crucial for balanced eye growth.

Animals↗

PubMed1995

Phenotyping of CYP2C19 with enantiospecific HPLC-quantification of R- and S-mephenytoin and comparison with the intron4/exon5 G-->A-splice site mutation.

S-Mephenytoin 4'-hydroxylase (CYP2C19) is a genetically polymorphic cytochrome P450. A modified method for CYP2C19 phenotyping was evaluated in 174 healthy German volunteers and the results were compared with genotyping for the intron4/exon5 G-->A splice site mutation (m1) of CYP2C19, associated with the poor metabolizer (PM) phenotype. A smaller than usual test-dose of 50 mg (R,S)-mephenytoin was used and urine samples were collected from 0 to 5 h and from 5 to 8 h after administration. Trait measurements included the mephenytoin S/R enantiomeric ratio and the hydroxylation index (i.e. the molar ratio of 4'-hydroxy-mephenytoin urinary recovery to the administered S-mephenytoin dose). S- and R-mephenytoin were quantified by isocratic HPLC with a Chiraspher column and 80% n-hexane and 20% dioxane as the mobile phase. All individuals from whom DNA was available (n = 140, including six phenotypically identified PMs) were analysed for the m1 mutation. The population frequency of this CYP2C19 mutation was 0.15. Four individuals were homozygous for m1 having S/R ratios of 0.9 or greater in both intervals of urine collection. Thus, individuals with an S/R ratio > or = 0.9 were classified as PMs and seven of all 174 phenotyped individuals were PMs (4%; 95% confidence limits: 1.6-8.1%). Heterozygous carriers of m1 (n = 34) had a median S/R ratio (5-8 h urine) of 0.06 compared to 0.01 in individuals without this mutation (n = 102; p = 0.0005, Mann-Whitney U-test). No such gene-dose relation was apparent with the hydroxylation index.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine↗

PubMed1997

Diagnosis strategies in activated protein C resistance: is genotyping still necessary?

Resistance to activated protein C (APC) is due, in most cases, to a G to A mutation at nucleotide 1691 of factor V (FV) gene (the Leiden mutation). This inherited abnormality is now considered to be the major hereditary cause associated with an elevated risk of thrombosis. For this reason, laboratories are faced with an increasing number of samples referred for APC resistance diagnosis. This could have serious economic consequences and a comprehensive laboratory screening strategy for APC resistance is necessary. An original DNA assay based on denaturing gradient gel electrophoresis (DGGE) was designed in our laboratory. During a first period we systematically performed DNA analysis and compared the results with phenotypic assays. Using the modified functional test with a 1:5 predilution of plasmas, the cut-off value for APC resistance ratio was 2.6 in our sample. Among 94 consecutive patients referred to our laboratory we found a clear cut-off between the APC resistance ratio obtained for normal and abnormal individuals. The modified test had a predictive value of 1.0 found by a cut-off < or = 2.6 for the heterozygote FV Leiden. This obviates the necessity of genotyping subjects with a normal phenotype. Among patients with an abnormal phenotype we were able to fully discriminate between homozygous and heterozygous patients using a cut-off value of 1.5. Nevertheless, our results demonstrate that, because of false-positive results such as lupus anticoagulant, genotyping is still indicated for patients with an abnormal ratio determined with the modified APC resistance test. The strategy described here allows us to safely lower the number of samples analysed by DGGE.

Blood Coagulation Disorders↗

PubMed2002

Mutational analysis reveals a role for the C terminus of the proteasome subunit Rpt4p in spindle pole body duplication in Saccharomyces cerevisiae.

The ubiquitin/proteasome pathway plays a key role in regulating cell cycle progression. Previously, we reported that a conditional mutation in the Saccharomyces cerevisiae gene RPT4/PCS1, which encodes one of six ATPases in the proteasome 19S cap complex/regulatory particle (RP), causes failure of spindle pole body (SPB) duplication. To improve our understanding of Rpt4p, we created 58 new mutations, 53 of which convert clustered, charged residues to alanine. Virtually all mutations that affect the N-terminal region, which contains a putative nuclear localization signal and coiled-coil motif, result in a wild-type phenotype. Nine mutations that affect the central ATPase domain and the C-terminal region confer recessive lethality. The two conditional mutations identified, rpt4-145 and rpt4-150, affect the C terminus. After shift to high temperature, these mutations generally cause cells to progress slowly through the first cell cycle and to arrest in the second cycle with large buds, a G2 content of DNA, and monopolar spindles, although this phenotype can vary depending on the medium. Additionally, we describe a genetic interaction between RPT4 and the naturally polymorphic gene SSD1, which in wild-type form modifies the rpt4-145 phenotype such that cells arrest in G2 of the first cycle with complete bipolar spindles.

Adenosine Triphosphatases↗

PubMed1993

Analysis of the c-FOS gene on chromosome 14 and the promoter of the amyloid precursor protein gene in familial Alzheimer's disease.

The c-FOS gene product, a putative transacting transcriptional regulator of the amyloid precursor protein (APP) gene, is a candidate locus for the familial Alzheimer's disease (FAD) mutation on chromosome 14 (FAD14). In light of this functional relationship, we investigated the nucleotide sequence and segregation of c-FOS and the nucleotide sequence of the 5' APP promoter. Single-stranded conformational polymorphisms (SSCPs) in the c-FOS gene revealed that c-FOS closely cosegregates with the FAD14 gene but does not show allelic association with FAD. A conservative third-position T-->C mutation was demonstrated in exon 2 (codon 84) of c-FOS, and a C-->G substitution was detected at -209 bp in the 5' promoter of APP. Neither were unique to FAD and are unlikely to be pathogenic or secondary modifiers of the FAD phenotype. We conclude that the c-FOS open reading frame is probably not the site of the FAD14 locus, but we cannot exclude the existence of modifier loci on chromosome 21.

Adult↗

PubMed2005

What have gonadotrophin overexpressing transgenic mice taught us about gonadal function?

The two gonadotrophins, follicle-stimulating hormone and luteinising hormone, are pivotal regulators of the development and maintenance of normal fertility by maintaining testicular and ovarian endocrine function and gametogenesis. Too low gonadotrophin secretion, i.e. hypogonadotrophic hypogonadism, is a common cause of infertility. But there are also physiological and pathophysiological conditions where gonadotrophin secretion and/or action are either transiently or chronically elevated, such as pregnancy, pituitary tumours, polycystic ovarian syndrome, activating gonadotrophin receptor mutations, perimenopause and menopause. These situations can be either the primary or secondary cause of infertility and gonadal pathologies in both sexes. Also the role of gonadotrophins as tumour promoters is possible. Recently, the possibility to combine information from genetically modified mice and human phenotypes in connection with mutations of gonadotrophin or gonadotrophin receptor genes has elucidated many less well known mechanisms involved in dysregulation of gonadotrophin function. Among the genetically modified mouse models, transgenic mice with gonadotrophin hypersecretion have been developed during the last few years. In this review, we describe the key findings on transgenic mouse models overexpressing gonadotrophins and present their possible implications in related human pathologies. In addition, we provide examples of genetic mouse models with secondary effects on gonadotrophin production and, consequently, on gonadal function.

Animals↗

PubMed1996

Dosage-dependent modification of position-effect variegation in Drosophila.

Many loci in Drosophila exhibit dosage effects on single phenotypes. In the case of modifiers of position-effect variegation, increases and decreases in dosage can have opposite effects on variegating phenotypes. This is seemingly paradoxical: if each locus encodes a limiting gene product sensitive to dosage decreases, then increasing the dosage of any one should have no effect, because the others should remain limiting. An earlier model put forward to resolve this paradox suggested that dosage-dependent modifiers encode protein subunits of a macromolecular complex that is sensitive to mass action equilibrium conditions. Because chemical equilibria are dynamic, however, such hypothetical complexes will be unstable to an extent that is inconsistent with the known properties of molecules that make up chromatin. An alternative model accounts for the dosage effects in terms of interactions between structural proteins that bind at multiple linked sites. These might include indirect interactions occurring between regulatory proteins and genes for structural proteins or their protein products. The large number of direct and inverse regulatory genes which are known to exist in Drosophila could account for the apparent genetic complexity that is seen for modifiers of position-effect variegation and for other systems of phenotypic modification.

Animals↗

PubMed2005

What can cell biology tell us about heterogeneity in lysosomal storage diseases?

UNLABELLED: Lysosomal storage diseases are clinically heterogeneous with respect to their age of onset, progression of symptoms and the particular organs involved. Varying levels of residual enzyme activity, associated with different defective alleles that cause the respective diseases, are responsible in part for this clinical heterogeneity. In general, the higher the residual enzyme activity, the milder the phenotype. Enzyme activity in severe forms of disease is frequently zero, and in mild forms usually does not exceed approximately 5%. However, the correlation is not so strict as to allow prediction of the phenotype of individual patients. The molecular basis of the different levels of enzyme activity can only be revealed by biochemical investigations of the defective lysosomal proteins. Null alleles may be due to splice-site mutations or deletions. In the case of missense mutations, enzymes frequently fold incorrectly and are retained in the endoplasmic reticulum and subsequently degraded. As these enzymes do not reach the lysosome, they do not provide any functional residual activity. Residual enzyme activity is only observed in cases where the defective enzyme reaches the lysosome and has retained enzymatic activity. Patients carrying the same mutant alleles still show considerable phenotypic variability due to modifying genes and epigenetic factors. None of these has so far been elucidated. However, there are some indications that differences in splicing-factor machinery may influence the phenotypic expression of splice-site mutations and that hormonal modulation of secondary microglial activation in lipidosis may also influence the disease course. CONCLUSION: Phenotypic variability is a frequent phenomenon in lysosomal storage diseases. Residual enzyme activity has been identified as one of the factors influencing the clinical outcome of disease; however, it is obvious that other genetic and epigenetic factors also affect phenotypic variability, particularly in patients with late onset disease.

Alleles↗

PubMed1998

The inducible prostaglandin biosynthetic enzyme, cyclooxygenase 2, is not mutated in patients with attenuated adenomatous polyposis coli.

Germ-line mutations in the APC gene cause adenomatous polyposis coli (APC), a syndrome in which patients develop hundreds to thousands of precancerous adenomatous colorectal polyps. We described previously an attenuated form of APC (AAPC) resulting from very 5' mutations in APC in which affected patients exhibit fewer colorectal polyps and a later age of onset of colorectal cancer. However, because striking variations in colorectal polyp numbers occur among patients carrying identical AAPC mutations, alleles of another gene may modify the expression of the APC disease phenotype. We tested the hypothesis that loss of function of human cyclooxygenase 2 (COX-2), known to modify the APC phenotype in the Apc delta716 mouse, results in a decreased tumor burden in AAPC patients that develop very few colorectal polyps. Genomic DNA sequence analysis of human COX-2 revealed a silent mutation in exon 3 that was evenly distributed between two classes of patients with AAPC, those with small or large numbers of colorectal polyps. We also found no difference in levels of COX-2 mRNA in transformed blood lymphocytes among AAPC patients of either class or patients with classical APC, and no alterations that correlated with a lesser or greater number of colorectal polyps were detectable within approximately the first 1 kb of the promoter sequence. Therefore, mutation of the human COX-2 gene does not appear to be responsible for a low tumor burden among AAPC subjects.

Adenomatous Polyposis Coli↗

PubMed2006

New ENU-induced semidominant mutation, Ali18, causes inflammatory arthritis, dermatitis, and osteoporosis in the mouse.

Inflammation is a complex cellular and humoral response against trauma and infection, and its presence leads to destruction of tissue in humans. The mechanisms that initiate inflammatory diseases remain largely unknown because of complex interactions between multiple genetic and environmental factors during pathogenesis. Animal models for human diseases offer dissection of complex pathogenesis by inbred genetic backgrounds and controlled circumstances. In this article we report a chemically induced new mutation, Ali18 (Abnormal limb), as a mouse model for inflammatory arthritis and dermatitis. Ali18/+ mice exhibit rubor and swelling of footpads in hindlimbs in adults. In Ali18/Ali18 mice, the digits in forelimbs and hindlimbs and tails were necrotic and/or deformed by severe swelling. Histologic analysis revealed infiltration of mixed populations of inflammatory cells into bone marrow, peripheral joints, and skin in the affected areas of Ali18/Ali18 mice. In addition, generalized osteoporosis-like phenotypes were confirmed by dual energy X-ray absorptiometry (DXA), microcomputed tomography (muCT), and peripheral quantitative computed tomography (pQCT) in homozygous animals. Whereas the Ali18 mutation was mapped to a single locus, the phenotype presentation was altered by complex modifier effects from other inbred genetic backgrounds. Detailed analysis of the Ali18 phenotype and identification of the mutation and its modifier genes may provide molecular insights into the complex nature of inflammatory diseases and the relationship between inflammation and bone metabolism.

Absorptiometry, Photon↗