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PubMed2001

Molecular and clinical evaluation of a patient hemizygous for TIGR/MYOC.

OBJECTIVE: To determine if a patient with an interstitial deletion of chromosome 1 is hemizygous for the TIGR/MYOC gene and if that patient has glaucoma. METHODS: A patient with an interstitial deletion of chromosome 1 was clinically examined for evidence of glaucoma. DNA samples from the patient and her family were used for molecular studies to determine the boundaries of the chromosome 1 deletion using polymorphic markers located on chromosome 1q21 to 1q24. Additional markers located in the vicinity of the TIGR/MYOC gene, including 2 derived from the ends of the gene, were used to determine if it was included in the deletion. RESULTS: The patient and her family showed no evidence of glaucoma. Molecular analysis demonstrated that a complex deletion of the maternal copy of chromosome 1 included the entire TIGR/MYOC gene. CONCLUSIONS: We have determined that the patient has only 1 functional copy of TIGR/MYOC. The lack of clinical evidence of glaucoma suggests that haploinsufficiency of the TIGR/MYOC protein is not the cause of early-onset glaucoma associated with mutations in TIGR/MYOC. CLINICAL RELEVANCE: Missense and nonsense mutations in the TIGR/MYOC gene have been associated with juvenile- and adult-onset primary open-angle glaucoma. Although many different mutations have been correlated with the disease, the underlying genetic mechanism (haploinsufficiency, gain of function, or a dominant negative effect) remains unknown. Information regarding the genetic mechanism responsible for TIGR/MYOC-associated glaucoma is necessary for further studies designed to develop transgenic animal models and gene-related therapy.

Adult↗
PubMed2004

Discrimination of single amino acid mutations of the p53 protein by means of deterministic singularities of recurrence quantification analysis.

p53 is mutated in roughly 50% of all human tumors, predominantly in the DNA-binding domain codons. Structural, biochemical, and functional studies have reported that the different p53 mutants possess a broad range of behaviors that include the elimination of the tumor-suppression function of wild-type protein, the acquisition of dominant-negative function over the wild-type form, and the establishment of gain-of-function activities. The contribution of each of these types of mutations to tumor progression, grade of malignancy, and response to anticancer treatments has been so far analyzed only for a few "hot-spots." In an attempt to identify new approaches to systematically characterize the complete spectrum of p53 mutations, we applied recurrence quantification analysis (RQA), a non-linear signal analysis technique, to p53 primary structure. Moving from the study of the p53 hydrophobicity pattern, which revealed important similarities with the singular deterministic structuring of prions, we could statistically discriminate, on a pure amino acid sequence basis, between experimentally characterized DNA-contact defective and conformational p53 mutants with a very high percentage of success. This result indicates that RQA is a mathematical tool particularly advantageous for the development of a database of p53 mutations that integrates epidemiological data with structural and functional categorizations.

Amino Acid Sequence↗
PubMed1987

Point mutations as an optimal search process in biological evolution.

Point mutations are pictured as jumps in a phase space representing the sequences of amino acids or nucleotides as discrete points. It is shown that this space can be given a natural metric by quantifying common physical and chemical properties of amino acid constituents in terms of a natural measure. Evolution through point mutations is simulated by the search for points in the phase space representing amino acid sequences of high survival fitness. Due to the local compactness of the distribution of these functionally allowed points in phase space any successful search procedure has characteristics qualitatively different from those in the case of a random distribution. This is demonstrated by model calculations. A specified distribution of allowed points is generated with subsequent evaluation of the success of the retrieval process as a function of the jump probabilities between lattice sites. The results of such simulations are compared with data obtained from the analysis of the DNA or mRNA sequences coding related proteins. By counting silent and expressed nucleotide replacement frequencies one can draw conclusions as to the efficacy of the natural evolutionary search processes in the phase space of amino acid sequences. There are cases, where the highest possible information gain of one bit per accepted point mutation is achieved. In general the information gain is found to be somewhat sub-maximal due to functional requirements.

Amino Acid Sequence↗
PubMed1998

Genotype-phenotype association in infants with cystic fibrosis at the time of diagnosis.

The relationship between the most common disease-causing mutations, the clinical manifestation, and lung function was prospectively assessed in 60 infants (33 females, 27 males) with cystic fibrosis at time of diagnosis (age: 7.2 months; range: 0.8-23.8 months). Lung function was assessed by infants whole-body plethysmography. Age at time of diagnosis was independent from the genotype. Weight gain from birth until the time of diagnosis expressed in percent predicted of a normal population was lower in the 3905insT group (57.9 +/- 19.0%) compared with deltaF508 homozygotes (62.5 +/- 20.6%; n.s.) and the R553X group (85.9 +/- 10.9%; p < 0.005). Differences regarding lung function within the genetic groups are mainly related to pulmonary hyperinflation, measured by thoracic gas volume (TGV), present in 8 of 9 infants with 3905insT, differentiating this frameshift mutation (TGV of 7.0 +/- 3.6 SD-S) from the R553X mutation (TGV 2.1 +/- 4.6 SD-S; p < 0.02). It is concluded that the variable disease findings in infants with cystic fibrosis is clinically and functionally reflected by features already present at time of diagnosis. The degree of pulmonary hyperinflation is, at least partly, influenced by the genotype.

Bacteria↗
PubMed2003

Genetic variations in the interleukin-12/interleukin-23 receptor (beta1) chain, and implications for IL-12 and IL-23 receptor structure and function.

Cell-mediated immunity (CMI) plays an essential role in human host defense against intracellular bacteria. Type-1 cytokines, particularly gamma interferon (IFN-gamma), interleukin-12 (IL-12), and IL-23, the major cytokines that regulate IFN-gamma production, are essential in CMI. This is illustrated by patients with unusual severe infections caused by poorly pathogenic mycobacteria and Salmonella species, in whom genetic deficiencies have been identified in several key genes in the type-1 cytokine pathway, including IL12RB1, the gene encoding the beta1 chain of the IL-12 and IL-23 receptors. Several mutations in IL12RB1 with deleterious effects on human IL-12R function have been identified, including nonsense and missense mutations. In addition, a number of coding IL12RB1 polymorphisms have been reported. In order to gain more insight into the effect that IL12RB1 mutations and genetic variations can have on IL-12Rbeta1 function, three approaches have been followed. First, we determined the degree of conservation at the variant amino acid positions in IL-12Rbeta1 between different species, using known deleterious mutations, known variations in IL-12Rbeta1, as well as novel coding variations that we have identified at position S74R and R156H. Second, we analyzed the potential impact of these amino acid variations on the three-dimensional structure of the IL-12Rbeta1 protein. Third, we analyzed the putative functions of different IL-12Rbeta1 domains, partly based on their homology with gp130, and analyzed the possible effects of the above amino acid variations on the function of these domains. Based on these analyses, we propose an integrated model of IL-12Rbeta1 structure and function. This significantly enhances our molecular understanding of the human IL-12 and IL-23 systems.

Alternative Splicing↗
PubMed2000

Genotype-based screen for ENU-induced mutations in mouse embryonic stem cells.

The ability to generate mutations is a prerequisite to functional genetic analysis. Despite a long history of using mice as a model system for genetic analysis, the scientific community has not generated a comprehensive collection of multiple alleles for most mouse genes. The chemical mutagen of choice for mouse has been N-ethyl-N-nitrosourea (ENU), an alkylating agent that mainly causes base substitutions in DNA, and therefore allows for recovery of complete and partial loss-, as well as gain-, of-function alleles . Specific locus tests designed to detect recessive mutations showed that ENU is the most efficient mutagen in mouse with an approximate mutation rate of 1 in 1,000 gametes. In fact, several genome-wide and region-specific screens based on phenotypes have been carried out. The anticipation of the completion of the human and mouse genome projects, however, now emphasizes genotype-driven genetics--from sequence to mutants. To take advantage of the mutagenicity of ENU and its ability to create allelic series of mutations, we have developed a complementary approach to generating mutations using mouse embryonic stem (ES) cells. We show that a high mutation frequency can be achieved and that modulating DNA-repair activities can enhance this frequency. The treated cells retain germline competency, thereby rendering this approach applicable for efficient generation of an allelic series of mutations pivotal to a fine-tuned dissection of biological pathways.

Amino Acid Substitution↗
PubMed2003

Transcriptional activation mediated by binding of a plant GATA-type zinc finger protein AGP1 to the AG-motif (AGATCCAA) of the wound-inducible Myb gene NtMyb2.

NtMyb2 is a regulator of the tobacco retrotransposon Tto1 and the defense-related gene phenylalanine ammonia lyase (PAL), which are induced by various stress stimuli such as wounding or elicitor treatment. NtMyb2 is also induced by wounding or elicitor treatment and is regulated at the transcriptional level. In this study, mutational analysis of the promoter of NtMyb2 and gain-of-function analysis in vivo showed that the sequence AGATCCAA, named the AG-motif, is a cis-element sufficient to confer responsiveness to wounding and elicitor treatment. Furthermore, by using the south-western method, we cloned cDNAs encoding a GATA-type zinc finger protein, which can specifically bind to the AG-motif, named AG-motif binding Protein (AGP1). Domain analysis revealed that not only the GATA-type zinc finger region but also the downstream His2 motif of AGP1 is required for binding activity, showing that the AGP has a novel GATA-type zinc finger domain. AGP1 can activate expression from promoters containing the AG-motif in tobacco protoplasts, indicating that AGP1 is a positive regulator of NtMyb2. We also found that the AGP1 binding activity is highly enhanced by adenine methylation of the AG-motif by bacterial dam methylase.

Amino Acid Sequence↗
PubMed1998

Association of multiple endocrine neoplasia type 2 and Hirschsprung disease.

In a few patients with Hirschsprung disease (HSCR) and no clinical symptoms of multiple endocrine neoplasia type 2 (MEN-2A) or medullary thyroid carcinoma (MTC), missense mutations in the cysteine residues 609 and 620 of the Ret gene have been identified. In several pedigrees with either MEN-2A or familial MTC (FMTC) a documented germline mutation in cysteine 618 or 620 follows the segregation of the disease phenotype. The appearance of the HSCR phenotype in such patients and pedigrees cannot be easily reconciled with the gain of function which is associated with the dominant oncogenic effect of MEN-2A mutations. Gastrointestinal manifestations are known to occur also in association with MEN-2B but, to the best of our knowledge, in only very few cases the intestinal phenotype of MEN-2B has been investigated by enzymo-histochemical techniques, as in the present work. We report an extensive molecular study of patients, two with HSCR and FMTC carrying a Cys620Arg or Ser mutation and two with MEN-2B and gastrointestinal symptoms carrying a Met918Thr mutation. One of the latter two patients showed aganglionosis of the last 5 cm of rectum which caused a congenital megacolon leading to the diagnosis and operation for HSCR. The mutation screening of all the exons of Ret in 3 of these patients did not reveal any additional mutation. Therefore these results do not support the hypothesis of additional constitutional Ret mutations in patients showing association of MEN-2 and HSCR, whilst the histochemical and clinical data in one of these patients indicate that MEN-2B can be associated with a true form of short segment HSCR.

Drosophila Proteins↗
PubMed2005

Further insights into the effect of quinidine in short QT syndrome caused by a mutation in HERG.

INTRODUCTION: The principal aim of this study was to assess the efficacy of quinidine in suppressing IKr in vitro and in modulating the rate dependence of the QT interval in the "SQT1" form of the short QT syndrome. METHODS AND RESULTS: Graded-intensity bicycle exercise testing was performed off drug in three patients and during oral quinidine in two patients with short QT syndrome and compared to a control group of healthy normal subjects. The in vitro effects of quinidine on currents in patch clamp technique were investigated. Off drugs QTpV3/heart rate correlation is much weaker in patients with short QT syndrome, and QTpV3 shortens less with heart rate increase compared to normal subjects. In addition to prolonging the QT interval into the normal range, quinidine restored the heart rate dependence of the QT interval toward a range of adaptation reported for normal subjects. Data from heterologous expression of wild-type and mutant HERG genes indicate the mutation causes a 20-fold increase in IC50 of d-sotalol but only a 5.8-fold increase in IC50 of quinidine. CONCLUSION: Oral quinidine is effective in suppressing the gain of function in IKr responsible for some cases of short QT syndrome with a mutation in HERG and thus restoring normal rate dependence of the QT interval and rendering ventricular tachycardia/ventricular fibrillation noninducible.

Adolescent↗
PubMed1989

Isolation and characterization of dominant female sterile mutations of Drosophila melanogaster. I. Mutations on the third chromosome.

Fifty-one dominant female sterile (Fs) mutations linked to the third chromosome of Drosophila melanogaster are described. EMS induced Fs mutations arise with the frequency of one Fs per about 2500 recessive lethals. Complementation analysis of the revertants showed that these Fs mutations represent 27-34 loci, about 60% of the third chromosome units mutable to dominant female sterility by EMS. The Fs mutations were mapped on the basis of mitotic recombination induced in the female (in 16 cases also in the male) germ-line. Behavior of the revertants and the Fs+ germ-line clones demonstrate the gain-of-function nature of the Fs alleles. With two exceptions, the Fs(3) mutations are germ-line dependent. Novel phenotypes appeared in most of the Fs mutations. With eight exceptions, the Fs(3) mutations are fully penetrant, in some cases with variable expressivity. One of the Fs(3) mutations is a non-ovary-dependent egg retention mutation, two others alter egg shape, and 27 bring about arrest in development at about the time of fertilization. In 21 of the Fs(3) mutations embryos develop to the larval stage of differentiation; this group includes 5 new alleles of Toll and 4 of easter.

Alleles↗
PubMed2005

Mechanisms of cell death in rhodopsin retinitis pigmentosa: implications for therapy.

Retinitis pigmentosa (RP) is a group of retinal degenerative diseases that are characterised primarily by the loss of rod photoreceptor cells. Mutations in rhodopsin are the most common cause of autosomal-dominant RP (ADRP). Here, we propose a new classification for rhodopsin mutations based on their biochemical and cellular properties. Several different potential gain-of-function mechanisms for rhodopsin ADRP are described and discussed. Possible dominant-negative mechanisms, which affect the processing, translocation or degradation of wild-type rhodopsin, are also considered. Understanding the molecular and cellular consequences of rod-opsin mutations and the underlying disease mechanisms in ADRP are essential to develop future therapies for this class of retinal dystrophies.

Amino Acid Sequence↗
PubMed2001

Familial Tetralogy of Fallot caused by mutation in the jagged1 gene.

Tetralogy of Fallot (ToF) is the most common form of complex congenital heart disease, occurring in approximately 1 in 3000 live births. Evaluation of candidate loci in a large kindred segregating autosomal dominant ToF with reduced penetrance culminated in identification of a missense mutation (G274D) in JAG1, the gene encoding jagged1, a Notch ligand expressed in the developing right heart. Nine of eleven mutation carriers manifested cardiac disease, including classic ToF, ventricular septal defect with aortic dextroposition and isolated peripheral pulmonic stenosis (PPS). All forms of ToF were represented, including variants with pulmonic stenosis, pulmonic atresia and absent pulmonary valve. No individual within this family met diagnostic criteria for any previously described clinical syndrome, including Alagille syndrome (AGS), caused by haploinsufficiency for jagged1. All mutation carriers had characteristic but variable facial features, including long, narrow and upslanting palpebral fissures, prominent nasal bridge, square dental arch and broad, prominent chin. This appearance was distinct from that of unaffected family members and typical AGS patients. The glycine corresponding to position 274 is highly conserved in other epidermal growth factor-like domains of jagged1 and in those of other proteins. Its substitution in other proteins has been associated with mild or atypical variants of disease. These data support either a relative loss-of-function or a gain-of-function pathogenetic mechanism in this family and suggest that JAG1 mutations may contribute significantly to common variants of right heart obstructive disease.

Amino Acid Sequence↗
PubMed2003

A naturally occurring p73 mutation in a p73-p53 double-mutant lung cancer cell line encodes p73 alpha protein with a dominant-negative function.

p73, a close homolog of p53 tumor suppressor, induces growth arrest and apoptosis. However, its role in cancers is controversial because of the rarity of p73 mutations, lack of tumors in p73-knockout mice, and the presence of multiple isotypes, among which Delta N isotypes inhibit the function of TA isotypes. We analyzed three naturally occurring p73 mutants found in lung cancer cell lines, NCI-H1155, DMS 92 and A427. NCI-H1155 is a cell line that has a p73 mutation [p73(G264W)] in the DNA-binding domain, as well as a p53 mutation [p53(R273H)], which is frequently found in human cancers and has a "gain-of-function" characteristic. p73 alpha(G264W) not only lacks transactivation activity itself, but also suppressed the transactivation activity of the wild-type p73 alpha in a dose-dependent manner, indicating that p73 alpha(G264W) is a dominant-negative mutant. p73 alpha(G264W) failed to suppress colony formation. We tested two other mutations, p73(Del418) in DMS 92 and p73(Del603) in A427. Both mutants retained similar levels of transactivation activity and suppression of colony formation to those of wild-type p73. The biological significance of these two mutations is unclear. In NCI-H1155 cells the coexistence of mutations that abrogate the normal functions of p73 and p53 may indicate that each mutation confers an additive growth advantage upon the cells.

Amino Acid Sequence↗
PubMed2001

Members of the tomato LeEIL (EIN3-like) gene family are functionally redundant and regulate ethylene responses throughout plant development.

The plant hormone ethylene regulates many aspects of growth, development and responses to the environment. The Arabidopsis ETHYLENE INSENSITIVE3 (EIN3) protein is a nuclear-localized component of the ethylene signal-transduction pathway with DNA-binding activity. Loss-of-function mutations in this protein result in ethylene insensitivity in Arabidopsis. To gain a better understanding of the ethylene signal-transduction pathway in tomato, we have identified three homologs of the Arabidopsis EIN3 gene (LeEILs). Each of these genes complemented the ein3-1 mutation in transgenic Arabidopsis, indicating that all are involved in ethylene signal transduction. Transgenic tomato plants with reduced expression of a single LeEIL gene did not exhibit significant changes in ethylene response; reduced expression of multiple tomato LeEIL genes was necessary to reduce ethylene sensitivity significantly. Reduced LeEIL expression affected all ethylene responses examined, including leaf epinasty, flower abscission, flower senescence and fruit ripening. Our results indicate that the LeEILs are functionally redundant and positive regulators of multiple ethylene responses throughout plant development.

Amino Acid Sequence↗
PubMed2006

Conversion of the low affinity ouabain-binding site of non-gastric H,K-ATPase into a high affinity binding site by substitution of only five amino acids.

P-type ATPases of the IIC subfamily exhibit large differences in sensitivity toward ouabain. This allows a strategy in which ouabain-insensitive members of this subfamily are used as template for mutational elucidation of the ouabain-binding site. With this strategy, we recently identified seven amino acids in Na,K-ATPase that conferred high affinity ouabain binding to gastric H,K-ATPase (Qiu, L. Y., Krieger, E., Schaftenaar, G., Swarts, H. G. P., Willems, P. H. G. M., De Pont, J. J. H. H. M., and Koenderink, J. B. (2005) J. Biol. Chem. 280, 32349-32355). Because important, but identical, amino acids were not recognized in that study, here we used the non-gastric H,K-ATPase, which is rather ouabain-insensitive, as template. The catalytic subunit of this enzyme, in which several amino acids from Na,K-ATPase were incorporated, was expressed with the Na,K-ATPase beta1 subunit in Xenopus laevis oocytes. A chimera containing 14 amino acids, located in M4, M5, and M6, which are unique to Na,K-ATPase, displayed high affinity ouabain binding. Four of these residues, all located in M5, appeared dispensable for high affinity binding. Individual mutation of the remaining 10 residues to their non-gastric H,K-ATPase counterparts yielded five amino acids (Glu312,Gly319, Pro778, Leu795, and Cys802) whose mutation resulted in a loss of ouabain binding. In a final gain-of-function experiment, we introduced these five amino acids in different combinations in non-gastric H,K-ATPase and demonstrated that all five were essential for high affinity ouabain binding. The non-gastric H,K-ATPase with these five mutations had a similar apparent affinity for ouabain as the wild type Na,K-ATPase and showed a 2000 times increased affinity for ouabain in the NH4+-stimulated ATPase activity in membranes of transfected Sf9 cells.

Amino Acid Sequence↗
PubMed1998

Naturally occurring genetic variation affects Drosophila photoreceptor determination.

The signal transduction pathway controlling determination of the identity of the R7 photoreceptor in the Drosophila eye is shown to harbor high levels of naturally occurring genetic variation. The number of ectopic R7 cells induced by the dosage-sensitive SevS11.1 transgene that encodes a mildly activated form of the Sevenless tyrosine kinase receptor is highly sensitive to the wild-type genetic background. Phenotypes range from complete suppression to massive overproduction of photoreceptors that exceeds reported effects of known single gene modifiers, and are to some extent sex-dependent. Signaling from the dominant gain-of-function Drosophila Epidermal Growth Factor Receptor (DER-Ellipse) mutations is also sensitive to the genetic backgrounds, but there is no correlation with the effects on SevS11.1. This implies that different genes and/or alleles modify the two activated receptor genotypes. The evolutionary significance of the existence of high levels of genetic variation in the absence of normal phenotypic variation is discussed.

Animals↗
PubMed1992

Mutant p53 can induce tumorigenic conversion of human bronchial epithelial cells and reduce their responsiveness to a negative growth factor, transforming growth factor beta 1.

Loss of normal functions and gain of oncogenic functions when the p53 tumor suppressor gene is mutated are considered critical events in the development of the majority of human cancers. Human bronchial epithelial cells (BEAS-2B) provide an in vitro model system to study growth, differentiation, and neoplastic transformation of progenitor cells of lung carcinoma. When wild-type (WT) or mutant (MT; codon 143Val-Ala) human p53 cDNA was transfected into nontumorigenic BEAS-2B cells, we observed that (i) transfected WT p53 suppresses and MT p53 enhances the colony-forming efficiency of these cells, (ii) MT p53 increases resistance to transforming growth factor beta 1, and (iii) clones of MT p53 transfected BEAS-2B cells are tumorigenic when inoculated into athymic nude mice. These results are consistent with the hypothesis that certain mutations in p53 may function in multistage lung carcinogenesis by reducing the responsiveness of bronchial epithelial cells to negative growth factors.

Animals↗
PubMed1998

Reduced fertility in female mice lacking copper-zinc superoxide dismutase.

Copper-zinc superoxide dismutase (CuZn-SOD) is believed to play a major role in the first line of antioxidant defense by catalyzing the dismutation of superoxide anion radicals to form hydrogen peroxide and molecular oxygen. Recent studies have shown that missense mutations in this gene contribute, evidently through a gain-of-function mechanism, to about 20% of familial amyotrophic lateral sclerosis. To define further the physiologic role of this enzyme, a model of mice deficient in this enzyme was generated using gene targeting technology. Mice lacking this enzyme were apparently healthy and displayed no increased sensitivity to hyperoxia. However, they exhibited a pronounced susceptibility to paraquat toxicity. Most surprisingly, female homozygous knock-out mice showed a markedly reduced fertility compared with that of wild-type and heterozygous knock-out mice. Further studies revealed that although these mice ovulated and conceived normally, they exhibited a marked increase in embryonic lethality. These data, for the first time, suggest a role of oxygen free radicals in causing abnormality of female reproduction in mammals.

Animals↗