scholarly journals Genetic background modifies vulnerability to glaucoma related phenotypes in Lmx1b mutant mice

2020 ◽  
Author(s):  
NG Tolman ◽  
DG Macalinao ◽  
AL Kearney ◽  
KH MacNicoll ◽  
CL Montgomery ◽  
...  
Keyword(s):  
Genetic Background ◽  
Anterior Segment ◽  
Nerve Damage ◽  
Mutant Mice ◽  
Genetic Modifiers ◽  
Modifier Locus ◽  
Homeobox Transcription Factor ◽  
Iop Elevation ◽  
New Treatments ◽  
Transcription Factor 1

AbstractVariants in the LIM homeobox transcription factor 1-beta gene (LMX1B) predispose individuals to elevated intraocular pressure (IOP), a key risk factor for glaucoma. However, the effect of LMX1B mutations varies widely between individuals. To better understand mechanisms underlying LMX1B-related phenotypes and individual differences, we backcrossed the Lmx1bV265D (also known as Lmx1bIcst) allele onto the C57BL/6J (B6), 129/Sj (129), C3A/BLiA-Pde6b+/J (C3H), and DBA/2J-Gpnmb+ (D2-G) strain backgrounds. Strain background had a significant effect on the onset and severity of ocular phenotypes in Lmx1bV265D/+ mutant mice. Mice of the B6 background were the most susceptible to developing elevated IOP, severe anterior segment developmental anomalies (including malformed eccentric pupils, iridocorneal strands, and corneal abnormalities) and glaucomatous nerve damage. In contrast, Lmx1bV265D mice of the 129 background were the most resistant to developing anterior segment abnormalities, had less severe IOP elevation than B6 mutants at young ages, and showed no detectable nerve damage. To identify genetic modifiers of susceptibility to Lmx1bV265D-induced glaucoma-associated phenotypes, we performed a mapping cross between mice of the B6 (susceptible) and 129 (resistant) backgrounds. We identified a modifier locus on Chromosome 18, with the 129 allele(s) substantially lessening severity of ocular phenotypes, as confirmed by congenic analysis. By demonstrating a clear effect of genetic background in modulating Lmx1b-induced phenotypes, by providing a panel of strains with different phenotypic severities and by identifying a modifier locus, this study lays a foundation for better understanding the roles of LMX1B in glaucoma with the goal of developing new treatments.

scholarly journals Genetic background modifies vulnerability to glaucoma-related phenotypes in Lmx1b mutant mice

2021 ◽  
Vol 14 (2) ◽  
pp. dmm046953
Author(s):  
Nicholas G. Tolman ◽  
Revathi Balasubramanian ◽  
Danilo G. Macalinao ◽  
Alison L. Kearney ◽  
Katharine H. MacNicoll ◽  
...  
Keyword(s):  
Genetic Background ◽  
Anterior Segment ◽  
Nerve Damage ◽  
Mutant Mice ◽  
Genetic Modifiers ◽  
Modifier Locus ◽  
Homeobox Transcription Factor ◽  
Iop Elevation ◽  
New Treatments ◽  
Transcription Factor 1

ABSTRACTVariants in the LIM homeobox transcription factor 1-beta (LMX1B) gene predispose individuals to elevated intraocular pressure (IOP), a key risk factor for glaucoma. However, the effect of LMX1B mutations varies widely between individuals. To better understand the mechanisms underlying LMX1B-related phenotypes and individual differences, we backcrossed the Lmx1bV265D (also known as Lmx1bIcst) allele onto the C57BL/6J (B6), 129/Sj (129), C3A/BLiA-Pde6b+/J (C3H) and DBA/2J-Gpnmb+ (D2-G) mouse strain backgrounds. Strain background had a significant effect on the onset and severity of ocular phenotypes in Lmx1bV265D/+ mutant mice. Mice of the B6 background were the most susceptible to developing abnormal IOP distribution, severe anterior segment developmental anomalies (including malformed eccentric pupils, iridocorneal strands and corneal abnormalities) and glaucomatous nerve damage. By contrast, Lmx1bV265D mice of the 129 background were the most resistant to developing anterior segment abnormalities, had less severe IOP elevation than B6 mutants at young ages and showed no detectable nerve damage. To identify genetic modifiers of susceptibility to Lmx1bV265D-induced glaucoma-associated phenotypes, we performed a mapping cross between mice of the B6 (susceptible) and 129 (resistant) backgrounds. We identified a modifier locus on Chromosome 18, with the 129 allele(s) substantially lessening severity of ocular phenotypes, as confirmed by congenic analysis. By demonstrating a clear effect of genetic background in modulating Lmx1b-induced phenotypes, providing a panel of strains with different phenotypic severities and identifying a modifier locus, this study lays a foundation for better understanding the roles of LMX1B in glaucoma with the goal of developing new treatments.

Abstract 3665: COL4A1 and COL4A2 Mutations cause Genetically Modifiable Cerebrovascular Diseases

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Marion Jeanne ◽  
Yi-Chinn Weng ◽  
Michelle de Leau ◽  
Cassandre Labelle-Dumais ◽  
Berkeley W Kauffman ◽  
...  
Keyword(s):  
Er Stress ◽  
Cell Biology ◽  
Phenotypic Variability ◽  
Cerebrovascular Diseases ◽  
Basement Membranes ◽  
Mutant Mice ◽  
Genetic Modifiers ◽  
Cellular Mechanisms ◽  
Cerebral Magnetic Resonance Imaging ◽  
Genetic Context

Mutations in the type IV collagen alpha 1 gene (COL4A1) cause Cerebrovascular Diseases (CVDs) in mice and human patients. Patients with COL4A1 mutations suffer from a broad range of CVDs, from infantile porencephaly to debilitating or fatal intracerebral hemorrhage (ICH), to subclinical cerebral microbleeds, suggesting that environmental and other genetic factors may influence their phenotypes. COL4A1 is one of the most abundant proteins in basement membranes and forms heterotrimers with COL4A2. Among possible pathogenic mechanisms are cellular stress due to the toxic intracellular aggregation of the COL4A1 and COL4A2 proteins and/or their absence in the basement membrane. Our first goal is to identify the relative contributions of COL4A1 and COL4A2 mutations to sporadic ICH and to understand the cellular mechanisms and genetic complexity underlying the disease. We identified novel COL4A1 mutations and for the first time, we discovered COL4A2 mutations in a cohort of 96 patients with sporadic ICH. Using a cell-based assay we determined that the mutations impair COL4A1 and COL4A2 secretion. We showed that mutant COL4A1 or COL4A2 proteins accumulate within the cell where they titrate normal COL4A1 and COL4A2 proteins. Interestingly, we found that some of the mutations can ultimately result in endoplasmic reticulum (ER) stress and activation of the Unfolded Protein Response. Our second goal was to test the hypothesis that differences in genetic context could contribute to phenotypic variability in human patients. Thus, we characterized CVD in Col4a1 mutant mice with two different genetic backgrounds. Using cerebral magnetic resonance imaging and histological analysis, we show that one or more genetic modifiers from the CAST/EiJ strain significantly reduce the size and frequency of ICHs detected in Col4a1 mutant mice on a C57BL/6J background. In conclusion, we found that both COL4A1 and COL4A2 mutations cause ICH in human patients, our results support that ER stress could be involved in the pathogenesis and we showed that genetic context is crucial for expressivity and severity of the CVD. We predict that ongoing experiments to better understand the cell biology of COL4A1 and COL4A2 mutations and the mechanisms of genetic modification could lead to targeted therapeutics to reduce the risk of CVD in patients with COL4A1 or COL4A2 mutations.

Functionality of cryopreserved juvenile ovaries from mutant mice in different genetic background strains after allotransplantation

Cryobiology ◽  
2010 ◽  
Vol 60 (2) ◽  
pp. 129-137 ◽  
Author(s):  
Kuo-Yu Huang ◽  
Suzanna A. de Groot ◽  
Henri Woelders ◽  
Gijsbertus T.J. van der Horst ◽  
Axel P.N. Themmen ◽  
...  
Keyword(s):  
Genetic Background ◽  
Mutant Mice ◽  
Different Genetic Background

scholarly journals Genetic background modulates behavioral impairments in R6/2 mice and suggests a role for dominant genetic modifiers in Huntington’s disease pathogenesis

2012 ◽  
Vol 23 (5-6) ◽  
pp. 367-377 ◽  
Author(s):  
Randi-Michelle Cowin ◽  
Nghiem Bui ◽  
Deanna Graham ◽  
Jennie R. Green ◽  
Lisa A. Yuva-Paylor ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Genetic Background ◽  
Genetic Modifiers ◽  
Disease Pathogenesis ◽  
Behavioral Impairments

scholarly journals Deletion of Ku70, Ku80, or Both Causes Early Aging without Substantially Increased Cancer

2007 ◽  
Vol 27 (23) ◽  
pp. 8205-8214 ◽  
Author(s):  
Han Li ◽  
Hannes Vogel ◽  
Valerie B. Holcomb ◽  
Yansong Gu ◽  
Paul Hasty
Keyword(s):  
Genetic Background ◽  
Double Mutant ◽  
Severe Combined Immunodeficiency ◽  
Nonhomologous End Joining ◽  
Mutant Mice ◽  
Combined Immunodeficiency ◽  
End Joining ◽  
High Incidence ◽  
Early Aging ◽  
Increased Sensitivity

ABSTRACT Ku70 forms a heterodimer with Ku80, called Ku, that is critical for repairing DNA double-stand breaks by nonhomologous end joining and for maintaining telomeres. Mice with either gene mutated exhibit similar phenotypes that include increased sensitivity to ionizing radiation and severe combined immunodeficiency. However, there are also differences in the reported phenotypes. For example, only Ku70 mutants are reported to exhibit a high incidence of thymic lymphomas while only Ku80 mutants are reported to exhibit early aging with very low cancer levels. There are two explanations for these differences. First, either Ku70 or Ku80 functions outside the Ku heterodimer such that deletion of one is not identical to deletion of the other. Second, divergent genetic backgrounds or environments influence the phenotype. To distinguish between these possibilities, the Ku70 and Ku80 mutations were crossed together to generate Ku70, Ku80, and double-mutant mice in the same genetic background raised in the same environment. We show that these three cohorts have similar phenotypes that most resemble the previous report for Ku80 mutant mice, i.e., early aging without substantially increased cancer levels. Thus, our observations suggest that the Ku heterodimer is important for longevity assurance in mice since divergent genetic backgrounds and/or environments likely account for these previously reported differences.

THE EFFECTS OF GENOTYPE AND TEMPERATURE ON THE RESISTANCE TO PUCCINIA GRAMINIS TRITICI CONTROLLED BY THE GENE Sr6 IN TRITICUM AESTIVUM

1981 ◽  
Vol 23 (2) ◽  
pp. 183-190 ◽  
Author(s):  
D. R. Knott
Keyword(s):  
Triticum Aestivum ◽  
Genetic Background ◽  
Triticum Aestivum L ◽  
Complex Interaction ◽  
Puccinia Graminis ◽  
Susceptible Parent ◽  
Puccinia Graminis Tritici ◽  
Modifier Locus ◽  
Maximum Resistance ◽  
Growth Chambers

A line of wheat (Triticum aestivum L.). Kenya 58/10* Marquis (K58Mq10), homozygous for gene Sr6 for resistance to stem rust (Puccinia graminis tritici Eriks. and Henn.), was crossed with four rust susceptible cultivars or lines. The F1 seedlings were tested with rust races 56 and 15B-1, twice under greenhouse conditions and three times in growth chambers, and F2 seedlings were tested twice in the greenhouse. In conditions that resulted in maximum resistance, Sr6 was dominant with both race 56 and race 15B-1 in two crosses, dominant with race 56 and recessive with race 15B-1 in one cross, and recessive with both races in the fourth cross. Thus, the dominance of Sr6 depended on the susceptible parent with which K58Mq10 had been crossed. The data indicated that the dominance of Sr6 was not controlled either by a single independent modifier locus or by the general genetic background of the susceptible parents. Although the possibility of a linked modifier has not been eliminated, it appears that the results may be due to the effects of different alleles for susceptibility at the Sr6 locus. The degree of resistance conditioned by Sr6 is determined by a complex interaction between genotype and environment.

scholarly journals Genetic background effects in Neuroligin-3 mutant mice: Minimal behavioral abnormalities on C57 background

2017 ◽  
Vol 11 (2) ◽  
pp. 234-244 ◽  
Author(s):  
Thomas C. Jaramillo ◽  
Christine Ochoa Escamilla ◽  
Shunan Liu ◽  
Lauren Peca ◽  
Shari G. Birnbaum ◽  
...  
Keyword(s):  
Genetic Background ◽  
Mutant Mice ◽  
Behavioral Abnormalities ◽  
Genetic Background Effects

scholarly journals Gpr63 is a novel modifier of microcephaly in Ttc21b mouse mutants

2018 ◽  
Author(s):  
J. Snedeker ◽  
WJ Gibbons ◽  
D.R. Prows ◽  
R.W. Stottmann
Keyword(s):  
Quantitative Trait ◽  
Genetic Background ◽  
Chromosome 6 ◽  
Chromosome 4 ◽  
Genetic Modifiers ◽  
Causal Gene ◽  
Mouse Mutants ◽  
Signaling Center ◽  
Trait Locus ◽  
G Protein Coupled

ABSTRACTThe primary cilium is a critical signaling center for proper embryonic development. Previous studies have demonstrated that mice lacking Ttc21b have impaired retrograde trafficking within the cilium and multiple organogenesis phenotypes, including microcephaly. Interestingly, the severity of the microcephaly in Ttc21baln/aln homozygous null mutants is considerably affected by the genetic background. Ttc21baln/aln mutants on an FVB/NJ background develop a forebrain significantly smaller than mutants on a C57BL/6J background. We performed a Quantitative Trait Locus (QTL) analysis to identify potential genetic modifiers and identified two regions linked to differential forebrain size: modifier of alien QTL1 (Moaq1) on chromosome 4 at 27.8 Mb and Moaq2 on chromosome 6 at 93.6 Mb. These QTLs were validated by constructing congenic strains. Further analysis of Moaq1 identified a brain specific orphan G-protein coupled receptor (GPCR), Gpr63, as a candidate gene. We identified a SNP between the FVB and B6 strains in Gpr63, which creates a missense mutation predicted to be deleterious in the FVB protein. We first demonstrated that Gpr63 can localize to the cilium and then used CRISPR-Cas9 genome editing to create FVB congenic mice with the B6 sequence of Gpr63 and a deletion allele leading to a truncation of the GPR63 C-terminal tail. These alleles genetically interact with Ttc21baln/aln, validating Gpr63 as a forebrain modifier of Ttc21b and strongly supporting Gpr63 as the variant causal gene (i.e., the quantitative trait gene, QTG) for Moaq1.

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