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At least 865 records · Page 48Linked to original sources
PubMed2006

Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome.

A clinically recognizable 9q subtelomeric deletion syndrome has recently been established. Common features seen in these patients are severe mental retardation, hypotonia, brachycephaly, flat face with hypertelorism, synophrys, anteverted nares, cupid bow or tented upper lip, everted lower lip, prognathism, macroglossia, conotruncal heart defects, and behavioral problems. The minimal critical region responsible for this 9q subtelomeric deletion (9q-) syndrome has been estimated to be <1 Mb and comprises the euchromatin histone methyl transferase 1 gene (EHMT1). Previous studies suggested that haploinsufficiency for EHMT1 is causative for 9q subtelomeric deletion syndrome. We have performed a comprehensive mutation analysis of the EHMT1 gene in 23 patients with clinical presentations reminiscent of 9q subtelomeric deletion syndrome. This analysis revealed three additional microdeletions that comprise the EHMT1 gene, including one interstitial deletion that reduces the critical region for this syndrome. Most importantly, we identified two de novo mutations--a nonsense mutation and a frameshift mutation--in the EHMT1 gene in patients with a typical 9q- phenotype. These results establish that haploinsufficiency of EHMT1 is causative for 9q subtelomeric deletion syndrome.

Abnormalities, Multiple↗
PubMed1996

Adsorptive or by pit formation endocytosis of immunoglobulins without loss of function as potential biotherapeutical application.

We here describe an alternative way to microinjection by which cellular transport of immunoglobulins through surface membranes can be achieved after binding to specific surface receptors either induced or constutively present, or via Fc receptors (Ig-mediated). In this report, the internalisation of two antibodies in two different cellular systems is analysed: the anti-p21ras monoclonal antibody (MoAb) after surface Ig binding on murine placental cells and anti-cdc2 MoAb that binds directly to its surface receptor expressed on the human promyelocytic leukemia cell line HL-60. In both cases, binding and internalisation is followed by Electron Microscopy (EM) and function is assessed by different assays. The first involves abrogation of class II antigen expression induced by Interferon-gamma (IFN-gamma) and 5-Azacytidine (5-AzaC) known to be mediated by activation of the ras pathway. The second involves growth cessation of HL-60 cells after antibody adsorption when a G1-S-specific culture supernatant containing anti-cdc2 activity is employed, whereas no growth hindrance is observed when a G2-M-specific anti-cdc2 MoAb is used. Thus, the antibodies do not follow the lysosyme pathway and do not lose their functional activity. This method may be applied in the future in order to achieve biological or clinical therapies.

Adsorption↗
PubMed1993

Loss of function of Saccharomyces cerevisiae kinesin-related CIN8 and KIP1 is suppressed by KAR3 motor domain mutations.

The kinesin-related products of the CIN8 and KIP1 genes of Saccharomyces cerevisiae redundantly perform an essential function in mitosis. The action of either gene-product is required for an outwardly directed force that acts upon the spindle poles. We have selected mutations that suppress the temperature-sensitivity of a cin8-temperature-sensitive kip1-delta strain. The extragenic suppressors analyzed were all found to be alleles of the KAR3 gene. KAR3 encodes a distinct kinesin-related protein whose action antagonizes Cin8p/Kip1p function. All seven alleles analyzed were altered within the region of KAR3 that encodes the putative force-generating (or "motor") domain. These mutations also suppressed the inviability associated with the cin8-delta kip1-delta genotype, a property not shared by a deletion of KAR3. Other properties of the suppressing alleles revealed that they were not null for function. Six of the seven were unaffected for the essential karyogamy and meiosis properties of KAR3 and the seventh was dominant for the suppressing trait. Our findings suggest that despite an antagonistic relationship between Cin8p/Kip1p and Kar3p, aspects of their mitotic roles may be similar.

Alleles↗
PubMed1996

Bayesian procedures for the estimation of mutation rates from fluctuation experiments.

Bayesian procedures are developed for estimating mutation rates from fluctuation experiments. Three Bayesian point estimators are compared with four traditional ones using the results of 10,000 simulated experiments. The Bayesian estimators were found to be at least as efficient as the best of the previously known estimators. The best Bayesian estimator is one that uses (1/m2) as the prior probability density function and a quadratic loss function. The advantage of using these estimators is most pronounced when the number of fluctuation test tubes is small. Bayesian estimation allows the incorporation of prior knowledge about the estimated parameter, in which case the resulting estimators are the most efficient. It enables the straightforward construction of confidence intervals for the estimated parameter. The increase of efficiency with prior information and the narrowing of the confidence intervals with additional experimental results are investigated. The results of the simulations show that any potential inaccuracy of estimation arising from lumping together all cultures with more than n mutants (the jackpots) almost disappears at n = 70 (provided that the number of mutations in a culture is low). These methods are applied to a set of experimental data to illustrate their use.

Bacteria↗
PubMed1998

Overexpression Beadex mutations and loss-of-function heldup-a mutations in Drosophila affect the 3' regulatory and coding components, respectively, of the Dlmo gene.

LIM domains function as bridging modules between different members of multiprotein complexes. We report the cloning of a LIM-containing gene from Drosophila, termed Dlmo, which is highly homologous to the vertebrate LIM-only (LMO) genes. The 3' untranslated (UTR) of Dlmo contains multiple motifs implicated in negative post-transcriptional regulation, including AT-rich elements and Brd-like boxes. Dlmo resides in polytene band 17C1-2, where Beadex (Bx) and heldup-a (hdp-a) mutations map. We demonstrate that Bx mutations disrupt the 3'UTR of Dlmo, and thereby abrogate the putative negative control elements. This results in overexpression of Dlmo, which causes the wing scalloping that is typical of Bx mutants. We show that the erect wing phenotype of hdp-a results from disruption of the coding region of Dlmo. This provides molecular grounds for the suppression of the Bx phenotype by hdp-a mutations. Finally, we demonstrate phenotypic interaction between the LMO gene Dlmo, the LIM homeodomain gene apterous, and the Chip gene, which encodes a homolog of the vertebrate LIM-interacting protein NLI/Ldb1. We propose that in analogy to their vertebrate counterparts, these proteins form a DNA-binding complex that regulates wing development.

Animals↗
PubMed2001

Loss-of-function mutations in SIP1 Smad interacting protein 1 result in a syndromic Hirschsprung disease.

Hirschsprung disease (HD) has been described in association with microcephaly, mental retardation and characteristic facial features, delineating a syndrome possibly caused by mutations localized at chromosome 2q22--q23. We have analyzed a de novo translocation breakpoint at 2q22 in one patient presenting with this syndrome, and identified a gene, SIP1, which is disrupted by this chromosomal rearrangement. SIP1 encodes Smad interacting protein 1, a new member of the delta EF1/Zfh-1 family of two-handed zinc finger/homeodomain transcription factors. We determined the genomic structure and expression of the human SIP1 gene. Further analysis of four independent patients showed that SIP1 is altered by heterozygous frameshift mutations causing early truncation of the protein. SIP1, among other functions, seems to play crucial roles in normal embryonic development of neural structures and neural crest. Its deficiency, in altering function of the TGF beta/BMP/Smad-mediated signalling cascade, is consistent with some of the dysmorphic features observed in this syndrome, in particular the enteric nervous system defect that underlies HD.

Abnormalities, Multiple↗
PubMed2005

Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease.

Recently targeted disruption of Omi/HtrA2 has been found to cause neurodegeneration and a parkinsonian phenotype in mice. Using a candidate gene approach, we performed a mutation screening of the Omi/HtrA2 gene in German Parkinson's disease (PD) patients. In four patients, we identified a novel heterozygous G399S mutation, which was absent in healthy controls. Moreover, we identified a novel A141S polymorphism that was associated with PD (P<0.05). Both mutations resulted in defective activation of the protease activity of Omi/HtrA2. Immunohistochemistry and functional analysis in stably transfected cells revealed that S399 mutant Omi/HtrA2 and to a lesser extent, the risk allele of the A141S polymorphism induced mitochondrial dysfunction associated with altered mitochondrial morphology. Cells overexpressing S399 mutant Omi/HtrA2 were more susceptible to stress-induced cell death than wild-type. On the basis of functional genomics, our results provide a novel link between mitochondrial dysfunction and neurodegeneration in PD.

Amino Acid Sequence↗
PubMed2003

A novel loss of function mutation in exon 10 of the FSH receptor gene causing hypergonadotrophic hypogonadism: clinical and molecular characteristics.

BACKGROUND: Inactivating mutations of the FSH receptor (FSHR) are a rare cause of hypergonadotrophic hypogonadism in women. Only one patient with primary amenorrhoea due to an FSHR gene mutation has been reported outside of Finland, where the prevalence of Ala189Val mutations is particularly high. METHODS AND RESULTS: Here, we describe the clinical, molecular genetic and functional characteristics associated with a novel inactivating mutation in exon 10 of the FSHR gene identified in a patient who presented with primary amenorrhoea at 17 years of age. The C to G transversion found at nucleotide 1043 causes a Pro348Arg substitution in the extracellular region of the FSHR and results in a mutant FSHR that is completely inactive in functional studies and that does not bind FSH. The proband exhibits apparent homozygosity for this recessive mutation. Her father is heterozygous for the mutation while analysis of exon 10 of the FSHR gene from her mother revealed only wild-type sequence. Chromosome painting was used to exclude deletions or rearrangements of 2p, and microsatellite markers did not show paternal uniparental isodisomy for this region. These findings suggest that the proband is hemizygous, with an inherited or de-novo microdeletion, or alternatively a de-novo gene conversion, of the accompanying FSHR allele. CONCLUSIONS: This case confirms the importance of the FSHR in female pubertal development and reproduction, and supports a relationship between phenotype and function for FSHR mutations.

Adolescent↗
PubMed2001

Gain- and loss-of-function of Rhp51, a Rad51 homolog in fission yeast, reveals dissimilarities in chromosome integrity.

Rad51 is crucial not only in homologous recombination and recombinational repair but also in normal cellular growth. To address the role of Rad51 in normal cell growth we investigated morphological changes of cells after overexpression of wild-type and a dominant negative form of Rad51 in fission yeast. Rhp51, a Rad51 homolog in Schizosaccharomyces pombe, has a highly conserved ATP-binding motif. Rhp51 K155A, which has a single substitution in this motif, failed to rescue hypersensitivity of a rhp51 mutant to methyl methanesulfonate (MMS) and UV, whereas it binds normally to Rhp51 and Rad22, a Rad52 homolog. Two distinct cellular phenotypes were observed when Rhp51 or Rhp51 K155A was overexpressed in normal cells. Overexpression of Rhp51 caused lethality in the absence of DNA-damaging agents, with acquisition of a cell cycle mutant phenotype and accumulation of a 1C DNA population. On the other hand, overexpression of Rhp51 K155A led to a delay in G(2) with decondensed nuclei, which resembled the phenotype of rhp51. The latter also exhibited MMS and UV sensitivity, indicating that Rhp51 K155A has a dominant negative effect. These results suggest an association between DNA replication and Rad51 function.

Adenosine Triphosphate↗
PubMed2002

A loss-of-function mutation in the rice KNOX type homeobox gene, OSH3.

KNOX homeodomain (HD) proteins encoded by KNOTTED1-like homeobox genes (KNOX genes) are thought to work as switches for cells to change from an indeterminate to a determinate state, although their direct functions are not clear. In the process of isolating KNOX genes from rice, we found that one gene, named OSH3, has two amino acid substitutions in three of the invariant amino acid residues in the HD of KNOX proteins. These amino acid substitutions are not universal in rice: two of the cultivars from the Indica variety of rice do not carry those substitutions but two of the cultivars from Japonica variety do. We tested the effect of these amino acid substitutions on their ability to form dimers and to induce abnormal morophologies when overexpressed in transgenic plants. We found that OSH3 without those substitutions can form dimers and can induce an abnormal phenotype in overexpression studies, and that OSH3 with those amino acid substitutions is defective in both. Based on these observations, we concluded that OSH3 from two of the cultivars from the Japonica variety could have lost its original function, or could have acquired a novel function by modifying the action of HD, or both.

Amino Acid Sequence↗
PubMed2000

Nafenopin causes protein kinase C-mediated serine phosphorylation and loss of function of connexin 32 protein in rat hepatocytes without aberrant expression or localization.

The characteristics and mechanism of the inhibition of connexin-mediated gap junctional communication by the non-genotoxic rodent hepatocarcinogen, nafenopin, has been studied in rat hepatocytes. Nafenopin caused a time- and concentration-dependent inhibition of dye coupling in hepatocytes as assessed by transfer of microinjected lucifer yellow. A half-maximum inhibitory effect of nafenopin occurred at approximately 50 microM, which was not cytotoxic. The inhibitory effect was reversible since a significant recovery of communication was observed 3 h after removal of the chemical. The protein kinase inhibitor Gö6976 prevented the inhibition of dye coupling, but a tyrosine kinase inhibitor (genistein) did not. Connexin 32 and 26 protein expression, as assessed by immunoblotting, was similar in nafenopin-treated hepatocytes compared to controls, with the exception that in a 10-h culture with nafenopin, the level of connexin 26 was elevated compared to controls. Immunohistochemistry indicated that the localization of plaques containing connexin 32 was not affected in hepatocytes by nafenopin. Immunoprecipitated connexin 32 was, however, detected by an anti-phosphoserine antibody following nafenopin treatment, but not in controls. This serine phosphorylation was prevented in the presence of Gö6976. The results give further support for a role of protein kinase C in the post-translational inactivation of connexin 32 function in rat hepatocytes by nafenopin.

Animals↗
PubMed2005

Epilepsy and sodium channel gene mutations: gain or loss of function?

Mutations in voltage-gated sodium channel genes (SCN1A, SCN2A, SCN1B) have been reported to be responsible for some epilepsies. Although studying such mutations to elucidate the disease mechanisms would be indispensable for the development of effective therapies, the functional consequences of these mutations remain controversial. Here, I propose a novel hypothesis for an epileptic disease mechanism which could drive the design of further studies to understand the molecular pathology of these diseases.

Epilepsy↗
PubMed2001

Congenital anomalies of the kidney and urinary tract--role of the loss of function mutation in the pluripotent angiotensin type 2 receptor gene.

PURPOSE: Recent studies of the human genome and genetic engineering experiments in mice revealed that congenital anomalies of the kidney and urinary tract commonly seen in newborns in various anatomical forms are polygenic disease, that is a disease caused by simultaneous defects in multiple genes. We discuss some possible genetic explanations of the classic theories of the formation of congenital kidney and urinary tract anomalies. MATERIALS AND METHODS: We reviewed classic and current theories regarding urinary tract development. Included in our review are recent results from our laboratory evaluating the genetic role of normal and abnormal urinary tract development. RESULTS: We observed a genetic abnormality that may explain many classic anatomical theories of congenital kidney and urinary tract anomalies. One of the genes involved in urinary tract ontogenesis is the angiotensin type 2 receptor gene, which is the "other" angiotensin receptor. While the type 1 receptor mediates essentially all known actions of angiotensin, including its hypertensive effect, relatively little is known about the angiotensin type 2 receptor. Careful dissection studies in mutant mouse embryos selectively lacking the angiotensin type 2 receptor gene revealed that this gene is pleiotropic, that is its defect causes not only ectopic ureteral budding from the wolffian duct, but also disturbance in other subsequent ontogenic events that are critical for the normal growth of the kidney and urinary tract. CONCLUSIONS: Many congenital anomalies of the kidney and urinary tract appear to share a common genetic cause. While these anomalies are caused by various genetic hits, abnormalities in the angiotensin type 2 receptor gene are often involved in this anomalous development. This review article offers a better understanding of the genetics involved in urinary tract development and ties some of the newly emerging genetic theories with classic anatomical theories.

Angiotensin II↗
PubMed1989

Loss of functional voltage-gated sodium channels in persistent mumps virus-infected PC12 cells.

Rat pheochromocytoma (PC12) cells, persistently infected with mumps virus (MV), failed to generate full-sized stimulus-evoked action potentials (SEAPs) when examined by intracellular electrophysiological recording techniques. Application of tetrodotoxin (TTX) had little or no effect on MV-reduced SEAPs, indicating that the number of functional voltage-gated Na+ channels was decreased or their operation was blocked by the virus. In contrast, MV-infected cells generated normal Ca2+ spikes when bathed in a solution containing TTX, tetraethylammonium ions and a high concentration (20 mM) of Ca2+. In addition, when infected cells bathed in TTX were superfused with Co2+ the SEAP profile reverted to that typical of PC12 cells with functional voltagegated K+ channels only. These observations indicate that MV affects voltage-gated Na+ channels, but spares voltage-gated Ca2+ and K+ channels of persistently infected cells.

Adrenal Gland Neoplasms↗
PubMed1998

Loss-of-function mutations in the mtr efflux system of Neisseria gonorrhoeae.

Resistance of Neisseria gonorrhoeae to antimicrobial hydrophobic agents (HAs) has been ascribed to the mtr (multiple transferable resistance) operon. This operon is composed of the mtrR gene, which encodes a transcriptional repressor (MtrR), and a three-gene complex (mtrCDE), which encodes cell envelope proteins (MtrC-MtrD-MtrE) that form an energy-dependent efflux pump. HA-hypersusceptible strains are often isolated from patients, but the genetic basis for such hypersusceptibility was heretofore unknown. The genetic basis of HA hypersusceptibility in laboratory-derived strains BR54 and BR87 was studied to learn if this trait could be linked to mutations in the mtr operon. Mutations in the mtrR gene of these strains that could be phenotypically suppressed by mutations in their mtrC or mtrD genes were identified. Thus, small deletions (4-10 bp) in the mtrC or mtrD genes of strains BR87 and BR54 that would result in the production of truncated efflux pump proteins that serve as a membrane fusion protein (MtrC) or transporter of HAs (MtrD) were found to be responsible for their HA-hypersusceptible property.

Amino Acid Sequence↗