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PubMed1981

Loss of functional large T-antigen and free viral genomes from cells transformed in vitro by polyoma virus after passage in vivo as tumor cells.

We have analyzed the state, arrangement, and expression of polyoma viral DNA sequences in a number of in vitro-transformed Fischer rat cells before and after growth in vivo as tumour cells. When the in vitro lines used to induce the tumors contained only a single insert of viral sequences and did not produce either a full-size 100,000-dalton (100K) large T-antigen or free viral genomes, no differences in the above-mentioned properties were observed. By contrast, in vitro cell lines containing multiple inserts of viral sequences, a functional 100K large T-antigen, and free viral genome induced tumor cells which displayed a reduced number of inserts of viral sequences and which did not produce either a functional 100K large T-antigen or free viral genomes. All of the in vitro lines and their tumor cell derivatives expressed the polyoma virus 55K middle and 22K small T-antigen species. Possible mechanisms for the selection in vivo against cells containing a functional 100K large T-antigen and consequently free viral genomes are discussed.

Animals↗
PubMed2006

Mapping of hereditary mixed polyposis syndrome (HMPS) to chromosome 10q23 by genomewide high-density single nucleotide polymorphism (SNP) scan and identification of BMPR1A loss of function.

BACKGROUND: Hereditary mixed polyposis syndrome (HMPS) is characterised by colonic polyps of mixed histological types that are autosomal dominantly inherited and eventually lead to colorectal cancer (CRC). Study of the molecular basis of HMPS will enhance our knowledge of the genetic basis of the mixed polyposis-carcinoma sequence in both hereditary and sporadic CRC. METHODS/RESULTS: We performed a genomewide linkage search on 15 members of a three-generation HMPS family using the GeneChip Human Mapping 10K Array and identified a 7 cM putative linkage interval on chromosome 10q23. Subsequently, 32 members from two HMPS families were typed with nine microsatellite markers spanning the region and the linkage was confirmed with a maximum multi-point logarithm of the odds (LOD) score of 4.6 (p<0.001). The 10q23.1-10q23.31 haplotypes segregate with the disease in both families. We screened for mutations in four candidate genes within the linkage region and identified an 11 bp deletion in the bone morphogenesis protein receptor 1A (BMPR1A) gene in one family. CONCLUSIONS: Our results indicate that BMPR1A mutation accounts for HMPS. The data suggest that inactivating BMPR1A can initiate colorectal tumourigenesis via the mixed polyposis-carcinoma sequence.

Adenomatous Polyposis Coli↗
PubMed1999

Cholesterol balance and metabolism in mice with loss of function of Niemann-Pick C protein.

Type C Niemann-Pick disease is due to a mutation in Niemann-Pick C (NPC) protein, a putative determinant of intracellular cholesterol transport. This study quantifies cholesterol balance in vivo across all tissues in mice with this defect. Cholesterol balance in the heterozygous animal is normal, but in the homozygous mouse the whole animal cholesterol pool expands continuously from birth, reaching 5, 442 mg/kg at 7 wk. The size of this pool in each organ is proportional to the rate at which each tissue clears low-density lipoprotein-cholesterol. Despite this expansion, however, cholesterol synthesis is increased so that whole animal synthesis equals 180 mg. day-1. kg-1. Forcing additional cholesterol into the liver through the clathrin-coated pit pathway increases the hepatic cholesterol pool in control mice, all of which is esterified, while there is a much greater increase in this pool in mutant mice, all of which is unesterified. These findings are consistent with the view that there is a block in sterol movement from the lysosome to the sites of regulation in NPC disease and have important implications for understanding the function of the NPC protein in intracellular cholesterol metabolism, in general, and in the brain, in particular.

Animals↗
PubMed2003

Hindlimb unloading-induced muscle atrophy and loss of function: protective effect of isometric exercise.

The primary objective of this study was to determine the effectiveness of isometric exercise (IE) as a countermeasure to hindlimb unloading (HU)-induced atrophy of the slow (soleus) and fast (plantaris and gastrocnemius) muscles. Rats were assigned to either weight-bearing control, 7-day HU (H7), H7 plus IE (I7), 14-day HU (H14), or H14 plus IE (I14) groups. IE consisted of ten 5-s maximal isometric contractions separated by 90 s, administered three times daily. Contractile properties of the soleus and plantaris muscles were measured in situ. The IE attenuated the HU-induced decline in the mass and fiber diameter of the slow-twitch soleus muscle, whereas the gastrocnemius and plantaris mass were not protected. These results are consistent with the mean electromyograph recordings during IE that indicated preferential recruitment of the soleus over the gastrocnemius and plantaris muscles. Functionally, the IE significantly protected the soleus from the HU-induced decline in peak isometric force (I14, 1.49 +/- 0.12 vs. H14, 1.15 +/- 0.07 N) and peak power (I14, 163 +/- 17 vs. H14, 75 +/- 11 mN.fiber length.s-1). The exercise protocol showed protection of the plantaris peak isometric force at H7 but not H14. The IE also prevented the HU-induced decline in the soleus isometric contraction time, which allowed the muscle to produce greater tension at physiological motoneuron firing frequencies. In summary, IE resulted in greater protection from HU-induced atrophy in the slow soleus than in the fast gastrocnemius or plantaris.

Animals↗
PubMed2004

Beta-cells in type 2 diabetes: a loss of function and mass.

Type 2 diabetes mellitus manifests itself in individuals who lose the ability to produce sufficient amounts of insulin to maintain normoglycaemia in the face of insulin resistance. The ability to secrete adequate amounts of insulin depends on beta-cell function and mass. Chronic hyperglycaemia is detrimental to pancreatic beta-cells, causing impaired insulin secretion and playing an essential role in the regulation of beta-cell turnover. This paper will address the effect of chronically elevated glucose levels on beta-cell turnover and function. In previous studies we have shown that elevated glucose concentrations induce apoptosis in human beta-cells due to an interaction between constitutively expressed Fas ligand and upregulated Fas. Human beta-cells produce interleukin (IL)-1beta in response to high glucose concentrations, independently of an immune-mediated process. This was antagonized by the IL-1 receptor antagonist (IL-1Ra), a naturally occurring anti-inflammatory cytokine also found in the beta-cell. Therefore the balance of IL-1beta and IL-1Ra may play a crucial role in the pathogenesis of diabetes. Inhibition of glucotoxicity represents a promising therapeutic stratagem in diabetes therapy to preserve functional beta-cell mass.

Animals↗
PubMed2004

Amino acid mutagenesis within ligand-binding loops in alpha v confers loss-of-function or gain-of-function phenotype on integrin alpha v beta 3.

The crystal structure of alpha(v)beta(3) in complex with a cyclic RGD-containing ligand has recently been demonstrated. However, the functional significance of each residue within ligand binding loops has not been fully elucidated. Here, by employing alanine-scanning mutagenesis, we have examined the functional role of ligand contact residues in alpha(v). Tyr178 --> Ala substitution (Tyr178Ala) and Asp218Ala abolished a monovalent ligand, WOW-1 Fab binding as well as soluble fibrinogen binding, which is in perfect agreement with the crystallography. However, Asp150Ala showed no or only a modest inhibition of ligand binding. In contrast, Tyr substitution at Ala215 (Ala215Tyr) increased WOW-1 Fab binding, suggesting that the substitution increased the integrin affinity. The adhesion assay to immobilized fibrinogen showed essentially the same data as obtained using soluble ligands. Our present data indicate that Tyr178 and Asp218, but not Asp150 in alpha(v) is critically involved in ligand-binding and that Ala215 could regulate the affinity of alpha(v)beta(3).

Amino Acid Substitution↗
PubMed2000

Loss of function and inhibitory effects of human CSX/NKX2.5 homeoprotein mutations associated with congenital heart disease.

CSX/NKX2.5 is an evolutionarily conserved homeodomain-containing (HD-containing) transcription factor that is essential for early cardiac development. Recently, ten different heterozygous CSX/NKX2.5 mutations were found in patients with congenital heart defects that are transmitted in an autosomal dominant fashion. To determine the consequence of these mutations, we analyzed nuclear localization, DNA binding, transcriptional activation, and dimerization of mutant CSX/NKX2.5 proteins. All mutant proteins were translated and located to the nucleus, except one splice-donor site mutant whose protein did not accumulate in the cell. All mutants that had truncation or missense mutations in the HD had severely reduced DNA binding activity and little or no transcriptional activation function. In contrast, mutants with intact HDs exhibit normal DNA binding to the monomeric binding site but had three- to ninefold reduction in DNA binding to the dimeric binding sites. HD missense mutations that preserved homodimerization ability inhibited the activation of atrial natriuretic factor by wild-type CSX/NKX2.5. Although our studies do not characterize the genotype-phenotype relationship of the ten human mutations, they identify specific abnormalities of CSX/NKX2.5 function essential for transactivation of target genes.

Cell Compartmentation↗
PubMed2003

Amyotrophic lateral sclerosis: a novel hypothesis involving a gained 'loss of function' in the JNK/SAPK pathway.

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that mainly affects motor neurons. Despite intensive research efforts inspired by the mile-stone discovery linking the Cu/Zn superoxide dismutase 1 (SOD1) gene to a subset of familial cases, the mechanisms underlying disease pathogenesis are still largely unknown. Nonetheless, the recent finding of a second gene associated with familial form of the disease, ALS2, is likely to be of great help in elucidating the key pathways involved in motor neuron degeneration. Here, we provide evidence that the JNK/SAPK pathway plays a critical neuroprotective role in susceptible motor neurons in ALS. The involvement of the JNK/SAPK pathway integrates our knowledge about these two known genetic factors into a single pathogenic pathway involved in both sporadic and familial ALS.

Amyotrophic Lateral Sclerosis↗
PubMed2005

Changes in gene expression associated with loss of function of the NSDHL sterol dehydrogenase in mouse embryonic fibroblasts.

Seven human disorders of postsqualene cholesterol biosynthesis have been described. One of these, congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome, results from mutations in the X-linked gene NADH sterol dehydrogenase-like (NSDHL) encoding a sterol dehydrogenase. A series of mutant alleles of the murine Nsdhl gene are carried by bare patches (Bpa) mice, with Bpa(1H) representing a null allele. Heterozygous Bpa(1H) females display skin and skeletal abnormalities in a distribution reflecting random X inactivation, whereas hemizygous male embryos die before embryonic day 10.5. To investigate the molecular basis of defects associated with perturbations in cholesterol biosynthesis, microarray analysis was performed comparing gene expression in embryonic fibroblasts expressing the Bpa(1H) allele versus wild-type (wt) cells. Labeled cDNAs from cells grown in normal serum or lipid-depleted serum (LDS) were hybridized to microarrays containing 22,000 mouse genes. Among 44 genes that showed higher expression in the Bpa(1H) versus wt cells grown in LDS, 11 function in cholesterol biosynthesis, 7 are involved in fatty acid synthesis, 3 (Srebp2, Insig1, and Orf11) encode sterol-regulatory proteins, and 2 (Ldlr and StarD4) are lipid transporters. Of the 21 remaining genes, 16 are known genes, some of which have been implicated previously in cholesterol homeostasis or lipid-mediated signaling, and 5 are uncharacterized cDNA clones.

3-Hydroxysteroid Dehydrogenases↗
PubMed2004

Blockade of PKCdelta proteolytic activation by loss of function mutants rescues mesencephalic dopaminergic neurons from methylcyclopentadienyl manganese tricarbonyl (MMT)-induced apoptotic cell death.

The use of methylcyclopentadienyl manganese tricarbonyl (MMT) as a gasoline additive has raised health concerns and increased interest in understanding the neurotoxic effects of manganese. Chronic exposure to inorganic manganese causes Manganism, a neurological disorder somewhat similar to Parkinson's disease. However, the cellular mechanism by which MMT, an organic manganese compound, induces neurotoxicity in dopaminergic neuronal cells remains unclear. Therefore, we systematically investigated apoptotic cell-signaling events following exposure to 3-200 microM MMT in mesencephalic dopaminergic neuronal (N27) cells. MMT treatment resulted in a time- and dose-dependent increase in reactive oxygen species generation and cell death in N27 cells. The cell death was preceded by sequential activation of mitochondrial-dependent proapoptotic events including cytochrome c release, caspase-3 activation, and DNA fragmentation, indicating that the mitochondrial-dependent apoptotic cascade primarily triggers MMT-induced apoptotic cell death. Importantly, MMT induced proteolytic cleavage of protein kinase Cdelta (PKCdelta), resulting in persistently increased kinase activity. The proteolytic activation of PKCdelta was suppressed by treatment with 100 microM Z-VAD-FMK and 100 microM Z-DEVD-FMK, suggesting that caspase-3 mediates the proteolytic activation of PKCdelta. Pretreatment with 100 microM Z-DEVD-FMK and 5 microM rottlerin (a PKCdelta inhibitor) also significantly attenuated MMT-induced DNA fragmentation. Furthermore, overexpression of either the kinase inactive dominant negative PKCdelta(K376R) mutant or the caspase cleavage resistant PKCdelta(D327A) mutant rescued N27 cells from MMT-induced DNA fragmentation. Collectively, these results demonstrate that the mitochondrial-dependent apoptotic cascade mediates apoptosis via proteolytic activation of PKCdelta in MMT-induced dopaminergic degeneration and suggest that PKCdelta may serve as an attractive therapeutic target in Parkinson-related neurological diseases.

Animals↗
PubMed2003

Genetic regulation of branching morphogenesis: lessons learned from loss-of-function phenotypes.

Branching morphogenesis, defined as growth and branching of epithelial tubules during embryogenesis, is a fundamental feature of renal, lung, mammary gland, submandibular gland, and pancreatic morphogenesis in mammals. Disruption of branching morphogenesis has been demonstrated to result in maldevelopment of some of these organs. Genetic studies performed in affected humans and mutant mice have implicated transcription factors, secreted growth factors, and cell surface signaling molecules as critical regulators of branching morphogenesis. These factors function within networks that appear to exert tight control over the number and location of branches. This review summarizes current knowledge regarding the molecular control of branching morphogenesis in vivo with particular emphasis on the genetic contribution to perturbed branching morphogenesis in mice and humans.

Animals↗
PubMed1999

Hypothalamic obesity: multiple routes mediated by loss of function in medial cell groups.

Cell groups of the medial hypothalamus are key to the regulation of energy balance. Functional disruption by colchicine injected in the hypothalamic arcuate (ARC), paraventricular (PVN), and ventromedial (VMN) cell groups produced increased food intake and obesity; disruption of the dorsomedial nuclei (DMN) produced decreased food intake. Colchicine in ARC or PVN increased food intake during both light and dark periods and increased cumulative food intake. By contrast, colchicine in VMN increased food intake only during the light, and cumulative food intake was not increased. Both leptin and insulin were elevated in the obese rats. Compared with sham, the slope of regression of leptin on insulin was increased by disruption of PVN and DMN but was not altered by disruption of VMN. ARC disruption abolished the relationship between leptin and insulin. Colchicine injected in the DMN did not cause obesity but altered feeding and the normal relationship between leptin, fat, and insulin, suggesting that blockade of signals, for example, from the lateral hypothalamus to DMN may disinhibit the normal medial hypothalamic drive to decrease energy stores. Changes in caloric efficiency with time after colchicine injections suggest that rats with both ARC and PVN disruption respond to signals of obesity, whereas rats with VMN disruption do not. These studies distinguish among functions in the four medial hypothalamic nuclei and suggest that interactions among them normally serve to regulate energy balance through alterations in food acquisition and storage.

Animals↗
PubMed1998

A homozygous inactivating mutation in the parathyroid hormone/parathyroid hormone-related peptide receptor causing Blomstrand chondrodysplasia.

We describe a patient with Blomstrand chondrodysplasia, a lethal genetic disorder characterized by extremely advanced endochondral bone maturation, in whom a homozygous missense mutation is present in the gene coding for the PTH/PTHrP receptor that leads to the substitution of a proline for a leucine in the N-terminal portion of the receptor (P132L). PTH-induced cAMP accumulation was severely reduced in COS-7 cells expressing P132L receptors compared to that of cells expressing wild-type receptors, and PTH-induced inositol phosphate accumulation was not detectable in cells expressing the mutant receptor. Similar results were obtained using PTHrP as an agonist. Maximal specific binding of radioiodinated [Tyr36]PTHrp(1-36) by cells transfected with the P132L receptor was < 10% of that observed for cells transfected with the wild-type receptor. Despite the reduction in radioligand binding to P132L receptors, the intensity and distribution of the fluorescent signal resulting from the expression of receptors fused to GFP were similar for cells transfected with the wild-type and mutant P132L receptors, suggesting a similar degree of cell surface expression. These results firmly establish the role of abnormalities in the PTH/PTHrP receptor in the pathogenesis of Blomstrand chondrodysplasia, and thereby confirm the importance of signaling through the PTH/PTHrP receptor in human fetal skeletal development. Because the amino-acid mutated in the patient described here is otherwise conserved in all mammalian class II G protein-coupled receptors, this abnormality may provide insights into structural features needed for the normal function of this family of receptors.

Animals↗
PubMed2004

Human loss-of-function gonadotropin-releasing hormone receptor mutants retain wild-type receptors in the endoplasmic reticulum: molecular basis of the dominant-negative effect.

The GnRH receptor (GnRHR) is a heptahelical G protein-coupled receptor found in the plasma membrane of pituitary gonadotropes. GnRHR mutants isolated from patients with hypogonadotropic hypogonadism (HH) are frequently mislocalized proteins that can be restored to function by pharmacological chaperones. Nonfunctional HH mutants inhibit ligand binding and ligand-activated second messenger production by wild-type (WT) receptor when both are coexpressed in vitro. In this study, confocal microscopy of fluorescently labeled GnRHR was used to show that the dominant-negative effect, which occurs for human (but not for rodent) GnRHR, results from WT receptor retention in the endoplasmic reticulum by mislocalized mutants. Mutants hGnRHR(E90K), hGnRHR(L266R), and hGnRHR(S168R) were selected for study because they are known to be fully rescuable, partially rescuable, or nonrescuable (respectively) by a specific pharmacological chaperone. This chaperone corrects folding errors and promotes correct intracellular routing. Using this drug we showed that correcting routing of the mutant protein also rescues the WT receptor. Because of the large number of human diseases that appear to be caused by defective protein folding and subsequent mislocalization, it is likely that endoplasmic reticulum retention is a common cause of dominant-negative actions for other diseases involving G protein-coupled receptors, as appears to be the case in HH and for which there exists a potential therapeutic agent.

Animals↗
PubMed2004

LAMA2 loss-of-function mutation in a girl with a mild congenital muscular dystrophy.

The authors report a girl with autosomal recessive congenital muscular dystrophy linked to chromosome 6 (MDC1A) who carries a homozygous out-of-frame deletion in exon 56 of the LAMA2 gene but has a mild phenotype. She is still ambulant at age 13 years, shows white matter abnormalities on MRI, and traces of laminin alpha2 in her muscle biopsy with one of three antibodies used. This patient suggests that modulating factors can be associated with a less severe clinical phenotype in MDC1A.

Adolescent↗