Genetic modifiers of otocephalic phenotypes inOtx2heterozygous mutant mice

Development ◽  
2002 ◽  
Vol 129 (18) ◽  
pp. 4347-4357 ◽  
Author(s):  
Takuichiro Hide ◽  
Jun Hatakeyama ◽  
Chiharu Kimura-Yoshida ◽  
E Tian ◽  
Naoki Takeda ◽  
...  
Keyword(s):  
Genetic Effect ◽  
Mutant Mice ◽  
Chromosome 2 ◽  
Genetic Modifiers ◽  
Lod Score ◽  
Craniofacial Malformations ◽  
Knock Out ◽  
Craniofacial Malformation ◽  
Replication Experiment ◽  
Significant Locus

Mice heterozygous for the Otx2 mutation display a craniofacial malformation, known as otocephaly or agnathia-holoprosencephaly complex. The severity of the phenotype is dependent on the genetic background of a C57BL/6 (B6) strain; most of the offspring of Otx2 knock-out chimeras, which are equivalent to the F1 of CBA and B6 strains, backcrossed with B6 females display reduction or loss of mandible, whereas those backcrossed with CBA females do not show noticeable phenotype at birth. The availability of phenotypically disparate strains renders identification of Otx2 modifier loci possible. In this study, a backcross of chimera with B6 was generated and genome-wide scans were conducted with polymorphic markers for non-mendelian distribution of alleles in Otx2 heterozygous mutant mice displaying abnormalities in the lower jaw. We identified one significant locus, Otmf18, between D18Mit68 and D18Mit120 on chromosomes 18, linked to the mandibular phenotype (LOD score 3.33). A similar replication experiment using a second backcross (N3) mouse demonstrated the presence of another significant locus, Otmf2 between D2Mit164 and D2Mit282 on chromosome 2, linked to the mandibular phenotype (LOD score 3.93). These two modifiers account for the distribution of the craniofacial malformations by the genetic effect between B6 and CBA strains. Moreover, Otmf2 contain a candidate gene for several diseases in mice and humans. These genetic studies involving an otocephalic mouse model appear to provide new insights into mechanistic pathways of craniofacial development. Furthermore, these experiments offer a powerful approach with respect to identification and characterization of candidate genes that may contribute to human agnathia-holoprosencephaly complex diseases.

A major suppressor of cell death, slm1, modifies the expression of the maize (Zea mays L.) lesion mimic mutation les23

Genome ◽  
2004 ◽  
Vol 47 (5) ◽  
pp. 961-969 ◽  
Author(s):  
Bryan W Penning ◽  
Gurmukh S Johal ◽  
Michael D McMullen
Keyword(s):  
Cell Death ◽  
Quantitative Trait ◽  
Chromosome 2 ◽  
Genetic Modifiers ◽  
Lesion Mimic ◽  
Cell Death Pathway ◽  
Delayed Initiation ◽  
Significant Locus ◽  
Trait Locus ◽  
Lesion Severity

Disease lesion mimics provide an excellent biological system to study the genetic basis of cell death in plants. Many lesion mimics show variation in phenotype expression in different genetic backgrounds. Our goal was to identify quantitative trait loci (QTL) modifying lesion mimic expression thereby identifying genetic modifiers of cell death. A recessive lesion mimic, les23, in a severe-expressing line was crossed to the maize inbred line Mo20W, a lesion-suppressing line, and an F2 population was developed for QTL analysis. In addition to locating les23 to the short arm of chromosome 2, this analysis detected significant loci for modification of lesion expression. One highly significant locus was found on the long arm of chromosome 2. The Mo20W allele at this QTL significantly delayed initiation of the lesion phenotype and decreased the final lesion severity. Other QTL with lesser effect affected severity of lesion expression without affecting lesion initiation date. Our results demonstrate that dramatic change in lesion phenotype can be controlled by a single major QTL. The presumed function of this QTL in normal plants is to regulate some aspect of the cell death pathway underlying the les23 phenotype.Key words: genetic background, quantitative trait locus, phenotype suppression, Mo20W, corn.

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.

Abstract 304: Global Transcriptional Effects of Vitamin A Deficiency on the Postnatal Heart

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Cristi L Galindo ◽  
Truc-Linh Tran ◽  
Xuyang Peng ◽  
Douglas B Sawyer ◽  
Mary Asson-Batres
Keyword(s):  
Vitamin A ◽  
Natriuretic Peptide ◽  
Heart Development ◽  
Ventricular Remodeling ◽  
Vitamin A Deficiency ◽  
Healing Process ◽  
Mutant Mice ◽  
Wound Healing Process ◽  
Gene Encoding ◽  
Knock Out

Vitamin A (VA) is the chemical precursor of retinoic acid (RA), which is critical for embryonic development and for growth, immunity, metabolism, and cell differentiation in postnatal regenerating systems such as skin, sensory organs, and stem cell niches in the brain. VA is also essential for embryonic heart development, and we hypothesized that Vitamin A might exert an effect on the postnatal heart similar to what is observed for other tissues. Here, we report the global transcriptional profiles of wild-type (WT) mice fed a VA sufficient diet (VAS) compared with retinyl acyl transferase (LRAT) knock-out mice fed either a VAS or VA deficient (VAD) diet. Knockout of the LRAT gene alone was sufficient to induce differential expression of 576 genes relative to WT. Feeding LRAT mutant mice a VAD diet resulted in a change in the relative expression levels of 257 genes relative to LRAT mutant mice fed a VAS diet. As expected, we observed transcriptional alterations related to Vitamin A metabolism, including an increase in the gene encoding cellular retinoid binding protein 7 and down-regulation of the retinol metabolic enzymes Cy1a2 and Cyp2a4. Importantly, several cardiac genes not previously known to require VA were perturbed, including the gene encoding B-type natriuretic peptide, which was down-regulated in mutant mice irrespective of diet, and A-type natriuretic peptide, which was decreased only in mice fed the VAD diet. There was also a striking effect of VAD on genes important for immune responses, which could have an impact on the wound healing process subsequent to injury of the heart. This is consistent with recent evidence that showed that Vitamin A deficiency influences post-infarct ventricular remodeling in rats. In summary, this is the first microarray study of Vitamin A deficiency in the postnatal heart, which suggests mechanisms by which Vitamin A depletion may alter myocardial maintenance and repair after injury.

scholarly journals QTL Mapping for Gray Leaf Spot Resistance in a Tropical Maize Population

Plant Disease ◽  
2016 ◽  
Vol 100 (2) ◽  
pp. 304-312 ◽  
Author(s):  
L. Liu ◽  
Y. D. Zhang ◽  
H. Y. Li ◽  
Y. Q. Bi ◽  
L. J. Yu ◽  
...  
Keyword(s):  
Flowering Time ◽  
Leaf Spot ◽  
Genetic Effect ◽  
Gray Leaf Spot ◽  
Chromosome 2 ◽  
Tropical Maize ◽  
Maize Breeding ◽  
Breeding Programs ◽  
Maize Population ◽  
Qtl Effects

A tropical gray leaf spot (GLS)-resistant line, YML 32, was crossed to a temperate GLS-susceptible line, Ye 478, to produce an F2:3 population for the identification of quantitative trait loci (QTL) associated with resistance to GLS. The population was evaluated for GLS disease resistance and flowering time at two locations in Yunnan province. Seven QTL using GLS disease scores and six QTL using flowering time were identified on chromosomes 2, 3, 4, 5, and 8 in the YML 32 × Ye 478 maize population. All QTL, except one identified on chromosome 2 using flowering time, were overlapped with the QTL for GLS disease scores. The results indicated that QTL for flowering time in this population strongly corresponded to QTL for GLS resistance. Among the QTL, qRgls.yaas-8-1/qFt.yaas-8 with the largest genetic effect accounted for 17.9 to 18.1 and 11.0 to 21.42% of variations for GLS disease scores and flowering time, respectively, and these should be very useful for improving resistance to GLS, especially in subtropical maize breeding programs. The QTL effects for resistance to GLS were predominantly additive in nature, with a dominance effect having been found for two QTL on the basis of joint segregation genetic analysis and QTL analysis.

Altered lymphoid development in mice deficient for the mAF4 proto-oncogene

Blood ◽  
2000 ◽  
Vol 96 (2) ◽  
pp. 705-710 ◽  
Author(s):  
Patricia Isnard ◽  
Nathalie Coré ◽  
Philippe Naquet ◽  
Malek Djabali
Keyword(s):  
Lymphoblastic Leukemia ◽  
Mutant Mice ◽  
Functional Study ◽  
Heterologous Proteins ◽  
Double Positive ◽  
Acute Leukemias ◽  
Knock Out ◽  
Severe Reduction ◽  
Single Positive

Some chromosomal translocations in acute leukemias involve the fusion of the trithorax-related protein Mll (also called HRX, All1, Htrx,) with a variety of heterologous proteins. In acute lymphoblastic leukemia associated with the t(4;11)(q21;q23) translocation, the4q21 gene that fuses with Mll is AF4. To gain insight into the potential role of AF4 in leukemogenesis and development, this gene was inactivated by homologous recombination in mice. As expected from the tissue distribution of the AF4 transcript, development of both B and T cells is affected in AF4 mutant mice. A severe reduction of the thymic double positive CD4/CD8 (CD4+/CD8+) population was observed; in addition most double- and single-positive cells expressed lower levels of CD4 and CD8 coreceptors. Most importantly, the reconstitution of the double-positive compartment by expansion of the double-negative cell compartment was severely impaired in these mutant mice. In the bone marrow pre-B and mature B-cell numbers are reduced. These results demonstrate that the function of the mAF4 gene is critical for normal lymphocyte development. This raises the possibility that the disruption of the normal AF4 gene or its association with Mll function by translocation may orient the oncogenic process toward the lymphoid lineage. This represents the first functional study using a knock-out strategy on one of the Mll partner genes in translocation-associated leukemias.

scholarly journals Dizygotic Twinning Is Not Linked to Variation at the α -Inhibin Locus on Human Chromosome 2*

2000 ◽  
Vol 85 (9) ◽  
pp. 3391-3395
Author(s):  
Grant W. Montgomery ◽  
David L. Duffy ◽  
Jeff Hall ◽  
Barbara R. Haddon ◽  
Masataka Kudo ◽  
...  
Keyword(s):  
Multiple Pregnancy ◽  
Racial Groups ◽  
Chromosome 2 ◽  
Lod Score ◽  
Α Subunit ◽  
Small Peak ◽  
Pcr Product ◽  
Exon 1 ◽  
Log Odds ◽  
Complete Exclusion

Abstract Natural multiple pregnancy in women leading to dizygotic (DZ) twins is familial and varies across racial groups, suggesting a genetic predisposition. Mothers of DZ twins have a higher incidence of spontaneous multiple ovulation and elevated FSH concentrations. FSH release is controlled by feedback of inhibin peptides from the ovary, and immunization against inhibin α-subunit results in an increased ovulation rate in animals. The inhibin α-subunit is therefore a candidate gene for mutations that may increase the frequency of DZ twinning. Restriction digests of a PCR product from exon 1 with the enzyme SpeI detects a C/T polymorphism at bp 128 with two alleles of 447 and 323/124 bp. The polymorphism was typed in 1125 individuals from 326 pedigrees with 717 mothers of spontaneous DZ twins. The α-inhibin locus mapped within 3 centimorgans of D2S164, and linkage with DZ twinning was excluded [decimal log odds ratio (LOD) score, −2.81 at θ = 0]. There was complete exclusion of linkage (LOD, less than −2) of a gene conferring relative risk 1.8 (λs, >1.8) across the chromosome, except at the p-terminus region and a small peak (maximum LOD score, 0.6) in the region of D2S151-D2S326. Analysis using either recessive or dominant models excluded linkage with DZ twinning in this population (LOD score, less than −2.5) across chromosome 2. We conclude that dizygotic twinning is not linked to variation in the α-inhibin locus. The results also suggest that mutations in other candidates on chromosome 2, including the receptor for FSH and the βB-inhibin subunit (INHBB) cannot be major contributors to risk for DZ twinning.

Fgf8 is Necessary for Normal Frontonasal Development

2008 ◽  
Vol 139 (2_suppl) ◽  
pp. P105-P105
Author(s):  
Maria Wittkopf ◽  
Steven L Goudy
Keyword(s):  
Growth Factor ◽  
Craniofacial Development ◽  
Mutant Mice ◽  
Craniofacial Skeleton ◽  
Craniofacial Malformations ◽  
Complex Process ◽  
Poor Differentiation ◽  
Pas Staining ◽  
Fgf8 Signaling

Problem Craniofacial development is a complex process. We explore the role of ectodermal Fgf8 during craniofacial development in mice. Fgf8 is a multi-functional growth factor known to induce cell migration and differentiation. We hypothesize that Fgf8 is necessary for frontonasal development. To determine its role, we selectively removed Fgf8 signaling in cells expressing the AP2 gene. Methods We generated AP2 Cre Fgf8 f/f R26R mice at e13–18. The embryos are harvested and fixed. They are dehydrated or saturated in 30% sucrose, then embedded in paraffin or OCT compound, respectively, for sectioning. The paraffin sections are used for morphologic examination following H&E and PAS staining. The cryosections are used for X-gal staining and immunofluorescence. Skeletal preparations are used to assess the craniofacial skeleton. Results AP2 Cre mice are examined identifying AP2 expression in the developing epithelium. Gross examination of the AP2 Cre Fgf8 f/f mice reveals severe mid-face shortening and micrognathia. These mice are nonviable due to their severe facial abnormalities. Close inspection reveals prominent eyes that appear normally formed but lack eyelids. The skeletal preparation of the AP2 Cre Fgf8 f/f mouse demonstrates almost absent mandibular development and hypoplastic maxilla. This correlates with the hypoplastic, ill-organized sinus cavities with lack of nasal septum development seen on histologic sections. Examination of the epithelium and oral mucosa of these mutant mice demonstrates a verrucous morphology with poor differentiation. Conclusion Fgf8 expression in the ectoderm appears to be necessary for frontonasal development in mice. Without epithelial Fgf8 expression, the craniofacial and epidermal development is severely affected. Future studies will further characterize the epithelial and mesenchymal phenotype of the AP2 Cre Fgf8 f/f mutant mice. Significance The Fibroblast Growth Factor (Fgf) family is involved in multiple steps of craniofacial formation. Further studies elucidating the specific roles of its members, including Fgf8, will help better understand and manage craniofacial malformations.

scholarly journals Generation and Characterization of the Drosophila melanogaster paralytic Gene Knock-Out as a Model for Dravet Syndrome

Life ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1261
Author(s):  
Andrea Tapia ◽  
Carlo N. Giachello ◽  
Martina Palomino-Schätzlein ◽  
Richard A. Baines ◽  
Máximo Ibo Galindo
Keyword(s):  
Drosophila Melanogaster ◽  
Motor Neurons ◽  
Sodium Current ◽  
Protein A ◽  
Dravet Syndrome ◽  
Genetic Modifiers ◽  
Membrane Excitability ◽  
Gene Encoding ◽  
Knock Out ◽  
New Treatments

Dravet syndrome is a severe rare epileptic disease caused by mutations in the SCN1A gene coding for the Nav1.1 protein, a voltage-gated sodium channel alpha subunit. We have made a knock-out of the paralytic gene, the single Drosophila melanogaster gene encoding this type of protein, by homologous recombination. These flies showed a heat-induced seizing phenotype, and sudden death in long term seizures. In addition to seizures, neuromuscular alterations were observed in climbing, flight, and walking tests. Moreover, they also manifested some cognitive alterations, such as anxiety and problems in learning. Electrophysiological analyses from larval motor neurons showed a decrease in cell capacitance and membrane excitability, while persistent sodium current increased. To detect alterations in metabolism, we performed an NMR metabolomic profiling of heads, which revealed higher levels in some amino acids, succinate, and lactate; and also an increase in the abundance of GABA, which is the main neurotransmitter implicated in Dravet syndrome. All these changes in the paralytic knock-out flies indicate that this is a good model for epilepsy and specifically for Dravet syndrome. This model could be a new tool to understand the pathophysiology of the disease and to find biomarkers, genetic modifiers and new treatments.

Human INHBB gene variant (c.1079T>C:p.Met360Thr) alters testis germ cell content, but does not impact fertility in mice

Endocrinology ◽  
2022 ◽  
Author(s):  
Brendan J Houston ◽  
Anne E O’Connor ◽  
Degang Wang ◽  
Georgia Goodchild ◽  
D Jo Merriner ◽  
...  
Keyword(s):  
Uniparental Disomy ◽  
Round Spermatid ◽  
Inhibin B ◽  
Mutant Mice ◽  
Chromosome 2 ◽  
Cell Content ◽  
Serum Hormone ◽  
In Vitro Biosynthesis ◽  
Circulating Levels

Abstract Testicular derived inhibin B (α/βB dimers) acts in an endocrine manner to suppress pituitary production of follicle stimulating hormone (FSH), by blocking the actions of activins (βA/B/βA/B dimers). Previously, we identified a homozygous genetic variant (c.1079T>C:p.Met360Thr) arising from uniparental disomy of chromosome 2 in the INHBB gene (βB-subunit of inhibin B and activin B) in a man suffering from infertility (azoospermia). In this study, we aimed to test the causality of the p.Met360Thr variant in INHBB and testis function. Here, we used CRISPR/Cas9 technology to generate Inhbb  M364T/M364T mice, where mouse INHBB p.Met364 corresponds with human p.Met360. Surprisingly, we found that the testes of male Inhbb  M364T/M364T mutant mice were significantly larger compared with those of aged-matched wildtype littermates at 12 and 24 weeks of age. This was attributed to a significant increase in Sertoli cell and round spermatid number and, consequently, seminiferous tubule area, in Inhbb  M364T/M364T males compared to wildtype males. Despite this testis phenotype, male Inhbb  M364T/M364T mutant mice retained normal fertility. Serum hormone analyses however, indicated that the Inhbb  M364T variant resulted in reduced circulating levels of activin B, but did not affect FSH production. We also examined the effect of this p.Met360Thr, and an additional INHBB variant (c.314C>T: p.Thr105Met) found in another infertile man, on inhibin B and activin B in vitro biosynthesis. It was found that both INHBB variants resulted in a significant disruption to activin B in vitro biosynthesis. Together, this analysis supports that INHBB variants that limit activin B production have consequences for testis composition in males.

Genetics of Maximal Walking Speed and Skeletal Muscle Characteristics in Older Women

2008 ◽  
Vol 11 (3) ◽  
pp. 321-334 ◽  
Author(s):  
Kristina M. Tiainen ◽  
Markus Perola ◽  
Vuokko M. Kovanen ◽  
Sarianna Sipilä ◽  
Katja A. Tuononen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Linkage Analysis ◽  
Older Women ◽  
Walking Speed ◽  
Genetic Effect ◽  
Functional Independence ◽  
Chromosome 15 ◽  
Lod Score ◽  
Cross Sectional ◽  
Leg Extensor Power

AbstractThe aim of this study was to examine whether maximal walking speed, maximal isometric muscle strength, leg extensor power and lower leg muscle cross-sectional area (CSA) shared a genetic effect in common. In addition, we wanted to identify the chromosomal areas linked to maximal walking speed and these muscle characteristics and also investigate whether maximal walking speed and these three skeletal muscle characteristics are regulated by the same chromosomal areas. We studied 217 monozygotic (MZ) and dizygotic (DZ) female twin pairs aged 66 to 75 years in the Finnish Twin Study on Aging study. The DZ pairs (94) were genotyped for 397 microsatellite markers in 22 autosomes and X-chromosome. Genetic modeling showed that, muscle CSA, strength, power and walking speed shared a genetic effect in common which accounted for 7% of the variation in CSA, 51% in strength, 37% in power and 35% in walking speed. The results of an explorative multipoint linkage analysis suggested that the highest LOD score found for each phenotype was 2.41 for walking speed on chromosome 13q22.1, 2.14 for strength on chromosome 15q14, 2.84 for power on chromosome 8q24.23, and 2.93 for muscle CSA on chromosome 20q13.31. Also a suggestive LOD score, 2.68, for muscle CSA was found on chromosome 9q34.3. The chromosomal areas of a suggestive linkage for strength and power partly overlapped LOD scores higher than 1.0 being seen for these phenotypes on chromosome 15. The present study was the first genome-wide linkage analysis to be conducted for these multifactorial and clinically important phenotypes underlying functional independence in older women.

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