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Results for “Loss of Function Mutation”

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PubMed2002

Loss-of-function variants of the human melanocortin-1 receptor gene in melanoma cells define structural determinants of receptor function.

The alpha-melanocyte-stimulating hormone (alphaMSH) receptor (MC1R) is a major determinant of mammalian skin and hair pigmentation. Binding of alphaMSH to MC1R in human melanocytes stimulates cell proliferation and synthesis of photoprotective eumelanin pigments. Certain MC1R alleles have been associated with increased risk of melanoma. This can be theoretically considered on two grounds. First, gain-of-function mutations may stimulate proliferation, thus promoting dysplastic lesions. Second, and opposite, loss-of-function mutations may decrease eumelanin contents, and impair protection against the carcinogenic effects of UV light, thus predisposing to skin cancers. To test these possibilities, we sequenced the MC1R gene from seven human melanoma cell (HMC) lines and three giant congenital nevus cell (GCNC) cultures. Four HMC lines and two GCNC cultures contained MC1R allelic variants. These were the known loss-of-function Arg142His and Arg151Cys alleles and a new variant, Leu93Arg. Moreover, impaired response to a superpotent alphaMSH analog was demonstrated for the cell line carrying the Leu93Arg allele and for a HMC line homozygous for wild-type MC1R. Functional analysis in heterologous cells stably or transiently expressing this variant demonstrated that Leu93Arg is a loss-of-function mutation abolishing agonist binding. These results, together with site-directed mutagenesis of the vicinal Glu94, demonstrate that the MC1R second transmembrane fragment is critical for agonist binding and maintenance of a resting conformation, whereas the second intracellular loop is essential for coupling to the cAMP system. Therefore, loss-of-function, but not activating MC1R mutations are common in HMC. Their study provides important clues to understand MC1R structure-function relationships.

Alleles↗

PubMed1998

Mechanisms of development of multiple endocrine neoplasia type 2 and Hirschsprung's disease by ret mutations.

The ret proto-oncogene encodes a receptor tyrosine kinase whose ligands belong to the glial cell line-derived neurotrophic factor (GDNF) protein family. Its germline mutations are responsible for the development of multiple endocrine neoplasia (MEN) types 2A and 2B and Hirschsprung's disease (HSCR). MEN2A and MEN2B mutations result in the constitutive activation of Ret by different molecular mechanisms. MEN2A mutations involve cysteine residues present in the Ret extracellular domain and induce disulfide-linked Ret dimerization on the cell surface. MEN2B mutations were identified in methionine 918 in the tyrosine kinase domain and activate Ret without dimerization, probably due to a conformational change of its catalytic core region. In contrast to MEN2 mutations, HSCR mutations represent loss of function mutations. We found that most of HSCR mutations detected in the extracellular domain impair the Ret cell surface expression. More interestingly, ret mutations in cysteines 618 and 620 were reported in several families who developed both MEN2A and HSCR. It was suggested that these mutations might have two biological effects on Ret function, leading to the development of different clinical phenotypes in the same patients.

Drosophila Proteins↗

PubMed1999

Genetic alterations in head and neck squamous cell carcinomas.

The genetic alterations observed in head and neck cancer are mainly due to oncogene activation (gain of function mutations) and tumor suppressor gene inactivation (loss of function mutations), leading to deregulation of cell proliferation and death. These genetic alterations include gene amplification and overexpression of oncogenes such as myc, erbB-2, EGFR and cyclinD1 and mutations, deletions and hypermethylation leading to p16 and TP53 tumor suppressor gene inactivation. In addition, loss of heterozygosity in several chromosomal regions is frequently observed, suggesting that other tumor suppressor genes not yet identified could be involved in the tumorigenic process of head and neck cancers. The exact temporal sequence of the genetic alterations during head and neck squamous cell carcinoma (HNSCC) development and progression has not yet been defined and their diagnostic or prognostic significance is controversial. Advances in the understanding of the molecular basis of head and neck cancer should help in the identification of new markers that could be used for the diagnosis, prognosis and treatment of the disease.

Carcinoma, Squamous Cell↗

PubMed1998

Growth, metastasis, and invasiveness of Drosophila tumors caused by mutations in specific tumor suppressor genes.

More than 50 genes have been identified in Drosophila by loss-of-function mutations that lead to overgrowth of specific tissues. Loss-of-function mutations in the lethal giant larvae, discs large, or brain tumor genes cause neoplastic overgrowth of larval brains and imaginal discs. In the present study, the growth and metastatic potential of tumors resulting from mutations in these genes were quantified. Overgrown brains and imaginal discs were transplanted into adults and beta-galactosidase accumulation was used as a marker to identify donor cells. Mutations in these three genes generated tumors with similar metastatic patterns. For brain tumors, the metastatic index (a measure we defined as the fraction of hosts that acquired secondary tumors normalized for the amount of primary tumor growth) of each of the three mutants was similar. Analysis of cell proliferation in mutant brains suggests that the tumors arise from a population of several hundred cells which represent only 1-2% of the cells in third instar larval brains. For imaginal disc tumors from lethal giant larvae and brain tumor mutants, it is shown for the first time that they can be metastatic and invasive. Primary imaginal disc tumors from lethal giant larvae and brain tumor mutants formed secondary tumors in 43 and 53% of the hosts, respectively, although the secondary tumors were, in general, smaller than the secondary tumors derived from primary brain tumors.

Animals↗

PubMed2002

[Molecular defects in plasma membrane hormone receptors].

The biological effects of hormones are mediated by plasma membrane receptors which transmit extracellular signals to the cytoplasm and nucleus. Mutations in plasma membrane receptors can affect normal signal transduction with loss-of-function mutations leading to hormone resistance and gain-of-function mutations leading to constitutive activation of signaling pathways. The loss-of-function mutations leading to familial hormone resistance disorders are germline in origin whereas the gain-of-function mutations leading to constitutively active receptors are somatic. G-protein coupled receptors (GPCR) comprise a large superfamily of proteins characterized by seven transmembrane-spanning segments and interaction with GTP-binding(G) proteins. Mutations in GPCRs have been associated with dwarfism, congenital hyperthyroidism or hypothyroidism, nephrogenic diabetes insipidus, obesity, resistance to TSH, LH, FSH and ACTH, Jansen's metaphyseal and Blomstrand's chondrodysplasia, autosomal dominant hypoparathyroidism, and neonatal severe hyperparathyroidism. Mutations in other families of receptors which are characterized into one spanning-transmembrane receptor can result in resistance to insulin, GH, leptin and AMH. This review summarizes the molecular defects in plasma membrane hormone receptors in a large number of clinical disorders.

Cell Membrane↗

PubMed2005

Functional confirmation of Gitelman's syndrome mutations in Japanese.

Gitelman's syndrome is an autosomal recessive inherited renal tubular disorder resulting from loss-of-function mutations in the thiazide-sensitive sodium chloride cotransporter gene (SLC12A3). We have previously reported that the combined allele frequency for the reported Gitelman's syndrome mutations is 0.0321. However, almost all of the reported Gitelman's syndrome mutations were from case reports without functional confirmation. In the present study, we assessed the functionality of the two most prevalent mutations in Japanese, T180K and L849H, using a mammalian cell expression system. Human SLC12A3 cDNA was transiently expressed in Chinese hamster ovary (CHO) cells under the control of a cytomegalo virus (CMV) promoter. The T180K and L849H mutations were introduced by site-directed mutagenesis. The activity of the Na+-Cl- cotransporter was assessed by measuring tracer 22Na+ uptake. While the T180K variation was just a polymorphism, the L849H mutation was confirmed to be a loss-of-function mutation and appears to be responsible for the Gitelman's syndrome. This observation may have very important clinical implications, since the allele frequency of this variation is 0.0126.

Animals↗

PubMed2000

p53 mutations and loss of p53 function confer multidrug resistance in neuroblastoma.

BACKGROUND: Neuroblastomas often acquire sustained drug resistance during therapy. Sensitivities to carboplatin, etoposide, or melphalan were determined for 18 neuroblastoma cell lines; eight were sensitive and ten were resistant. As p53 mutations are rare in neuroblastomas studied at diagnosis, we determined if acquired p53 mutations and loss of function conferred multidrug resistance. RESULTS: Loss of p53 function (p53-LOF), defined as a failure to induce p21 and/or MDM2 in response to melphalan, was seen in 1/8 drug-sensitive and 6/10 drug-resistant cell lines. In four cell lines p53-LOF was associated with mutations in the DNA binding region of p53, while three cell lines with LOF and four cell lines with functional p53 had no evidence of p53 muta-tions. Nonfunctional and mutated p53 was detected in one resistant cell line, while a sensitive cell line derived from the same patient prior to treatment had functional and wild type (wt) p53. We transfected HPV 16 E6 (which mediates degradation of p53, causing LOF) into two drug-sensitive neuroblastoma cell lines with functional p53. LC(90) values of HPV 16 E6 transfected cell lines were 3-7-fold (melphalan), 8-109-fold (carboplatin), and 2-158-fold (etoposide) greater than that of LXSN-transfected controls. CONCLUSIONS: These data suggest that some neuroblastomas acquire p53 mutations during therapy, which is associated with a loss of p53 function, and can confer high-level multidrug resistance.

Chromosome Deletion↗

PubMed2006

Progressive cardiac conduction defect is the prevailing phenotype in carriers of a Brugada syndrome SCN5A mutation.

INTRODUCTION: Loss-of-function mutations in the SCN5A gene encoding the cardiac sodium channel are responsible for Brugada syndrome (BS) and also for progressive cardiac conduction disease (inherited Lenègre disease). In an attempt to clarify the frontier between these two entities, we have characterized cardiac conduction defect and its evolution with aging in a cohort of 78 patients carrying a SCN5A mutation linked to Brugada syndrome. METHODS AND RESULTS: Families were included in the study if a SCN5A mutation was identified in a BS proband and if at least two family members were mutation carriers. Sixteen families met the study criteria, representing 78 carriers. Resting ECG showed a spontaneous BS ECG pattern in 28 of 78 (36%) gene carriers. Intraventricular conduction anomalies were identified in 59 of 78 gene carriers including complete (17) or incomplete (24) right bundle branch block, right bundle branch block plus hemiblock (6), left bundle branch block (1), hemiblock (1), and parietal block (10). PR and QRS duration were longer in the gene carrier cohort in comparison with their relatives carrying no mutation. Finally, in the gene carrier cohort conduction defect progressively aggravated with aging leading in five occasions to pacemaker implantations. CONCLUSION: The present study shows that the most common phenotype of gene carriers of a BS-type SCN5A mutation is progressive cardiac conduction defects similar to the Lenègre disease phenotype. In consequence, we propose that carriers of a SCN5A mutation need a clinical and ECG follow-up because of the risk associated with severe conduction defects.

Adolescent↗

PubMed1991

Molecular genetics of the Posterior sex combs/Suppressor 2 of zeste region of Drosophila: aberrant expression of the Suppressor 2 of zeste gene results in abnormal bristle development.

We report the molecular characterization of the Posterior sex combs-Suppressor 2 of zeste region of Drosophila melanogaster. The distal breakpoint of the Aristapedioid inversion divides the region into two parts. We have molecularly mapped the lesions associated with several loss of function mutations in the Polycomb group gene Posterior sex combs (Psc) proximal to this breakpoint. In addition, we have found that lesions associated with several loss of function mutations in the Suppressor 2 of zeste [Su(z)2] gene lie distal to this breakpoint. Since the breakpoint does not cause a loss of function in either gene, no essential sequences are shared by these two neighboring genes. There are three dominant gain of function mutations in the region that result in abnormal bristle development. We find that all three juxtapose foreign DNA sequences upstream of the Su(z)2 gene, and that at least two of these mutations (Arp1 and vgD) behave genetically as gain of function mutations in Su(z)2. Northern and in situ hybridization analyses show that the mutations result in increased accumulation of the Su(z)2 mRNA, which we argue is responsible for the bristle loss phenotype.

Animals↗

PubMed2005

DNA-binding domain mutations in SMAD genes yield dominant-negative proteins or a neomorphic protein that can activate WG target genes in Drosophila.

Mutations in SMAD tumor suppressor genes are involved in approximately 140,000 new cancers in the USA each year. At this time, how the absence of a functional SMAD protein leads to a tumor is unknown. However, clinical and biochemical studies suggest that all SMAD mutations are loss-of-function mutations. One prediction of this hypothesis is that all SMAD mutations cause tumors via a single mechanism. To test this hypothesis, we expressed five tumor-derived alleles of human SMAD genes and five mutant alleles of Drosophila SMAD genes in flies. We found that all of the DNA-binding domain mutations conferred gain-of-function activity, thereby falsifying the hypothesis. Furthermore, two types of gain-of-function mutation were identified - dominant negative and neomorphic. In numerous assays, the neomorphic allele SMAD4(100T) appears to be capable of activating the expression of WG target genes. These results imply that SMAD4(100T) may induce tumor formation by a fundamentally different mechanism from other SMAD mutations, perhaps via the ectopic expression of WNT target genes - an oncogenic mechanism associated with mutations in Adenomatous Polyposis Coli. Our results are likely to have clinical implications, because gain-of-function mutations may cause tumors when heterozygous, and the life expectancy of individuals with SMAD4(100T) is likely to be different from those with other SMAD mutations. From a larger perspective, our study shows that the genetic characterization of missense mutations, particularly in modular proteins, requires experimental verification.

Animals↗

PubMed2005

Mutational analysis of the NPHP4 gene in 250 patients with nephronophthisis.

Nephronophthisis (NPH), a recessive cystic kidney disease, is the most frequent genetic cause for end-stage renal disease in the first two decades of life. Mutations in three genes (NPHP1, 2, and 3) were identified as causative. Extrarenal manifestations are known, such as retinitis pigmentosa (Senior-Loken syndrome, SLS) and ocular motor apraxia type Cogan. Recently, we identified a novel gene (NPHP4) as mutated in NPH. To date, a total of only 13 different NPHP4 mutations have been described. To determine the frequency of NPHP4 mutations, we performed mutational analysis by direct sequencing of all 30 NPHP4 exons in 250 different patients with isolated NPH, SLS, or Cogan syndrome ascertained worldwide over 14 years. We identified 23 novel NPHP4 sequence variants in 26/250 different patients (10%). Interestingly, we detected homozygous or compound heterozygous mutations of NPHP4 in only 6/250 different patients (2.4%), but only one heterozygous NPHP4 sequence variant in 20/250 different patients (8%). In the six patients with two NPHP4 mutations, 5/8 mutations (63%) were likely loss-of-function mutations, whereas in the 20 patients with only one sequence variant, only 1/20 (5%) was a likely loss-of-function (i.e., truncating) mutation. We conclude that: i) two recessive mutations in NPHP4 are a rare cause of nephronophthisis; ii) single heterozygous NPHP4 sequence variants are three times more prevalent than two recessive mutations; iii) there is no genotype/phenotype correlation; iv) there must exist further genes causing nephronophthisis, since in 224/250 (90%) patients, no sequence variants in either of the four NPH genes were detected.

Adolescent↗

PubMed2001

A new h allele detected in Europe has a missense mutationin alpha(1,2)-fucosyltransferase motif II.

BACKGROUND: The FUT1 gene encodes an alpha(1,2)-fucosyltransferase (H transferase), which determines the blood group H. Nonfunctional alleles of this gene, called h alleles and carrying loss-of-function mutations, are observed in the exceedingly rare Bombay phenotype. Twenty-three distinct h alleles have been characterized at the molecular level in various populations. The FUT2 (SE) gene is highly homologous to FUT1 (H:). STUDY DESIGN AND METHODS: The FUT1 gene of an Austrian proband with the Bombay phenotype was characterized by nucleotide sequencing of the full-length coding sequence. A PCR method using sequence-specific primers for FUT2 genotyping in whites was developed. The plasma alpha(1,2)-fucosyltransferase activity was determined. The distribution of the mutations underlying 24 h alleles and 7 se alleles was analyzed. RESULTS: The proband carried a new h allele. Two nucleotide changes, G785A and C786A, in codon 262 of the FUT1 gene resulted in the replacement of serine by lysine. No alpha(1,2)-fucosyltransferase activity was detected in the proband's plasma. The proband was homozygous for the seG428A allele. Six of 17 missense mutations in nonfunctional h and se alleles occurred in highly conserved fucosyltransferase motifs. No loss-of-function mutation was observed in the aminoterminal section encompassing the transmembraneous helix. CONCLUSION: The missense mutation S262K in the FUT1 gene caused the loss of H transferase activity. The analysis of the distribution of mutations in nonfunctional FUT1 and FUT2 genes can point to functionally important domains in the H transferase.

ABO Blood-Group System↗

PubMed2004

Relaxation of selective constraint and loss of function in the evolution of human bitter taste receptor genes.

Bitter taste perception prevents mammals from ingesting poisonous substances because many toxins taste bitter and cause aversion. We hypothesize that human bitter taste receptor (TAS2R) genes might be relaxed from selective constraints because of the change in diet, use of fire and reliance on other means of toxin avoidance that emerged in human evolution. Here, we examine the intra-specific variations of all 25 genes of the human TAS2R repertoire. Our data show hallmarks of neutral evolution, including similar rates of synonymous (d(S)) and non-synonymous (d(N)) nucleotide changes among rare polymorphisms, common polymorphisms and substitutions; no variation in d(N)/d(S) among functional domains; segregation of pseudogene alleles within species and fixation of loss-of-function mutations. These results, together with previous findings of large numbers of loss-of-function mutations in olfactory, pheromonal and visual sensory genes in humans, suggest surprisingly reduced sensory capabilities of humans in comparison with many other mammals.

Africa↗

PubMed2006

Functions of the nonsense-mediated mRNA decay pathway in Drosophila development.

Nonsense-mediated mRNA decay (NMD) is a cellular surveillance mechanism that degrades transcripts containing premature translation termination codons, and it also influences expression of certain wild-type transcripts. Although the biochemical mechanisms of NMD have been studied intensively, its developmental functions and importance are less clear. Here, we describe the isolation and characterization of Drosophila "photoshop" mutations, which increase expression of green fluorescent protein and other transgenes. Mapping and molecular analyses show that photoshop mutations are loss-of-function mutations in the Drosophila homologs of NMD genes Upf1, Upf2, and Smg1. We find that Upf1 and Upf2 are broadly active during development, and they are required for NMD as well as for proper expression of dozens of wild-type genes during development and for larval viability. Genetic mosaic analysis shows that Upf1 and Upf2 are required for growth and/or survival of imaginal cell clones, but this defect can be overcome if surrounding wild-type cells are eliminated. By contrast, we find that the PI3K-related kinase Smg1 potentiates but is not required for NMD or for viability, implying that the Upf1 phosphorylation cycle that is required for mammalian and Caenorhabditis elegans NMD has a more limited role during Drosophila development. Finally, we show that the SV40 3' UTR, present in many Drosophila transgenes, targets the transgenes for regulation by the NMD pathway. The results establish that the Drosophila NMD pathway is broadly active and essential for development, and one critical function of the pathway is to endow proliferating imaginal cells with a competitive growth advantage that prevents them from being overtaken by other proliferating cells.

Animals↗

PubMed2004

Genetic analysis of contributions of dorsal group and JAK-Stat92E pathway genes to larval hemocyte concentration and the egg encapsulation response in Drosophila.

Drosophila larvae defend themselves against parasitoid wasps by completely surrounding the egg with layers of specialized hemocytes called lamellocytes. Similar capsules of lamellocytes, called melanotic capsules, are also formed around "self" tissues in larvae carrying gain-of-function mutations in Toll and hopscotch. Constitutive differentiation of lamellocytes in larvae carrying these mutations is accompanied by high concentrations of plasmatocytes, the major hemocyte class in uninfected control larvae. The relative contributions of hemocyte concentration vs. lamellocyte differentiation to wasp egg encapsulation are not known. To address this question, we used Leptopilina boulardi to infect more than a dozen strains of host larvae harboring a wide range of hemocyte densities. We report a significant correlation between hemocyte concentration and encapsulation capacity among wild-type larvae and larvae heterozygous for mutations in the Hopscotch-Stat92E and Toll-Dorsal pathways. Larvae carrying loss-of-function mutations in Hopscotch, Stat92E, or dorsal group genes exhibit significant reduction in encapsulation capacity. Larvae carrying loss-of-function mutations in dorsal group genes (including Toll and tube) have reduced hemocyte concentrations, whereas larvae deficient in Hopscotch-Stat92E signaling do not. Surprisingly, unlike hopscotch mutants, Toll and tube mutants are not compromised in their ability to generate lamellocytes. Our results suggest that circulating hemocyte concentration and lamellocyte differentiation constitute two distinct physiological requirements of wasp egg encapsulation and Toll and Hopscotch proteins serve distinct roles in this process.

Animals↗

PubMed2005

Genetic analysis reveals domain interactions of Arabidopsis Hsp100/ClpB and cooperation with the small heat shock protein chaperone system.

We have defined amino acids important for function of the Arabidopsis thaliana Hsp100/ClpB chaperone (AtHsp101) in acquired thermotolerance by isolating recessive, loss-of-function mutations and a novel semidominant, gain-of-function allele [hot1-4 (A499T)]. The hot1-4 allele is unusual in that it not only fails to develop thermotolerance to 45 degrees C after acclimation at 38 degrees C, but also is sensitive to 38 degrees C, which is a permissive temperature for wild-type and loss-of-function mutants. hot1-4 lies between nucleotide binding domain 1 (NBD1) and NBD2 in a coiled-coil domain that is characteristic of the Hsp100/ClpB proteins. We then isolated two classes of intragenic suppressor mutations of hot1-4: loss-of-function mutations (Class 1) that eliminated the 38 degrees C sensitivity, but did not restore thermotolerance function to hot1-4, and Class 2 suppressors that restored acquired thermotolerance function to hot1-4. Location of the hot1-4 Class 2 suppressors supports a functional link between the coiled-coil domain and both NBD1 and the axial channel of the Hsp100/ClpB hexamer. In addition, the strongest Class 2 suppressors restored solubility of aggregated small heat shock proteins (sHsps) after heat stress, revealing genetic interaction of the Hsp100/ClpB and sHsp chaperone systems. These results also demonstrate that quantitative phenotypes can be used for in vivo genetic dissection of protein mechanism in Arabidopsis.

Alleles↗

PubMed2004

Kit as a human oncogenic tyrosine kinase.

Signals through Kit receptor tyrosine kinase are essential for development of erythrocytes, melanocytes, germ cells, mast cells and interstitial cells of Cajal (ICCs). Mice and rats with a double gene dose of loss-of-function mutations of Kit show depletion of these cells. Although human homozygotes with loss-of-function mutations of Kit have not been reported, gain-of-function mutations of Kit result in development of tumors from mast cells, germ cells and ICCs in humans. The ICC tumors are called gastrointestinal stromal tumors (GISTs), and GISTs are a good target for the Kit inhibitor imatinib mesylate. The interrelationship between the type of Kit gain-of-function mutations and the therapeutic effect of imatinib mesylate has been well characterized in GISTs. Kit is interesting from both a biological and clinical view-point.

Animals↗

PubMed2006

Identification of an agent selectively targeting DPC4 (deleted in pancreatic cancer locus 4)-deficient pancreatic cancer cells.

One of the most common types of genetic alterations in cancer is the loss-of-function mutations in tumor-suppressor genes. Such mutations are usually very specific to cancer cells and present attractive and unique opportunities for therapeutic interventions. However, for various reasons, antitumor agents that target loss-of-function mutations have not been readily identified. In this report, using the deleted in pancreatic cancer locus 4 (DPC4) gene in pancreatic cancer as an example, we show the feasibility of a novel screening strategy, which we have named Pharmacological Synthetic Lethal Screening, for the identification of agents that selectively target cancer cells with loss-of-function mutations. We created DPC4 isogenic cell lines through the restoration of wild-type DPC4 in a pancreatic cancer cell line, BxPC-3, whose DPC4 gene was homozygously deleted. The isogenic cell lines were then used in the Pharmacological Synthetic Lethal Screening to evaluate compound libraries for antiproliferative activity and selectivity against DPC4 deficiency. After screening 19,590 compounds, we identified one lead compound, UA62001, which showed 4.6-fold selectivity against DPC4 deficiency in the DPC4 isogenic cell lines. UA62001 selectivity was also seen in another set of DPC4 isogenic cell lines generated by small interfering RNA knockdown. In addition, UA62001 was evaluated in commonly used pancreatic cancer cell lines. A fairly good correlation between DPC4 deficiency and UA62001 sensitivity was observed. Cell cycle analysis indicates that UA62001 arrests cells in S and G(2)-M phases. The results of microarray gene expression profiling and quantitative real-time reverse transcription-PCR suggest that cyclin B/CDC2 and minichromosome maintenance complexes might be the downstream cellular targets of UA62001.

Adenocarcinoma↗