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PubMed1995

Amyotrophic lateral sclerosis associated with homozygosity for an Asp90Ala mutation in CuZn-superoxide dismutase.

Recent reports have shown heterozygosity for some twenty different mutations in the CuZn-superoxide dismutase (CuZn-SOD) gene in familial amyotrophic lateral sclerosis (FALS), and analysed samples from patients have shown decreased enzymic activity. Here we report homozygosity for an exon 4 mutation, Asp90Ala in fourteen patients among four unrelated ALS families and four apparently sporadic ALS patients from Sweden and Finland. The erythrocyte CuZn-SOD activity is essentially normal. Our findings suggest that this CuZn-SOD mutation causes ALS by a gain of function rather than by loss, and that the Asp90Ala mutation is less detrimental than previously reported mutations.

Adult↗
PubMed1993

Exploring the homeobox.

In Drosophila, homeotic mutations lead to the transformation of structures of one body segment into the corresponding structures of another segment. These mutations identify master regulator genes which specify segmental identity along the antero-posterior body axis. Dominant gain and recessive loss-of-function mutations generate to opposite segmental transformations. The cloning of the homeotic Antennapedia (Antp) gene led to the discovery of the homeobox, a 180-bp DNA segment characteristic for homeotic genes. It encodes the DNA-binding domain of the respective proteins which was designated as the homeodomain. Homeodomain proteins are transcriptional regulators which specify the body plan by controlling the transcription of their subordinate target genes. By inserting the Antp cDNA into a heat-inducible expression vector, the body plan can be altered in a predictable way. Using the homeobox as a probe, homologous Hox genes from vertebrates have been cloned. In the mouse, dominant gain and recessive loss-of-function mutations result in segmental transformations of opposite direction, as in Drosophila. Also, the mouse Hox genes can partially substitute the homologous Drosophila genes in transgenic flies. Therefore, the genetic control of the body plan is much more universal than anticipated. The three-dimensional structure of the Antp homeodomain and its complex with a consensus DNA-binding site was determined by nuclear magnetic resonance (NMR) spectroscopy. The homeodomain essentially consists of four alpha-helices, a helix-turn-helix motif, and a flexible N-terminal arm. Base-specific contacts are made by both the recognition helix and the N-terminal arm.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

A large homozygous or heterozygous in-frame deletion within the calcium-sensing receptor's carboxylterminal cytoplasmic tail that causes autosomal dominant hypocalcemia.

Autosomal dominant hypocalcemia (ADH) can result from heterozygous missense activating mutations of the calcium-sensing receptor (CaSR) gene, a G-protein-coupled receptor playing key roles in mineral ion metabolism. We now describe an ADH kindred of three generations caused by a novel CaSR mutation, a large in-frame deletion of 181 amino acids within its carboxylterminal-tail from S895 to V1075. Interestingly, the affected grandfather is homozygous for the deletion but no more severely affected than heterozygous affected individuals. Functional properties of mutant and wild-type (WT) CaSRs were studied in transiently transfected, fura-2-loaded human embryonic kidney (HEK293) cells. The mutant receptor exhibited a gain-of-function, but there was no difference between cells transfected with mutant complementary DNA alone or cotransfected with mutant and WT complementary DNAs, consistent with the similar phenotypes of heterozygous and homozygous family members. Therefore, this activating deletion may exert a dominant positive effect on the WT CaSR. The mutant receptor's cell surface expression was greater than that of the WT CaSR, potentially contributing to its gain-of-function. This novel mutation in the CaSR gene provides the first known examples of a large naturally occurring deletion within a G-protein-coupled receptor's carboxylterminal-tail and of a homozygous, affected individual with ADH.

Adult↗
PubMed1996

A beta-subunit mutation in the acetylcholine receptor channel gate causes severe slow-channel syndrome.

Point mutations in the genes encoding the acetylcholine receptor (AChR) subunits have been recognized in some patients with slow-channel congenital myasthenic syndromes (CMS). Clinical, electrophysiological, and pathological differences between these patients may be due to the distinct effects of individual mutations. We report that a spontaneous mutation of the beta subunit that interrupts the leucine ring of the AChR channel gate causes an eightfold increase in channel open time and a severe CMS characterized by severe endplate myopathy and extensive remodeling of the postsynaptic membrane. The pronounced abnormalities in neuromuscular synaptic architecture and function, muscle fiber damage and weakness, resulting from a single point mutation are a dramatic example of a mutation having a dominant gain of function and of hereditary excitotoxicity.

Adult↗
PubMed1997

Behavioral defects in C. elegans egl-36 mutants result from potassium channels shifted in voltage-dependence of activation.

Mutations in the C. elegans egl-36 gene result in defective excitation of egg-laying and enteric muscles. Dominant gain-of-function alleles inhibit enteric and egg-laying muscle contraction, whereas a putative null mutation has no observed phenotype. egl-36 encodes a Shaw-type (Kv3) voltage-dependent potassium channel subunit. In Xenopus oocytes, wild-type egl-36 expresses noninactivating channels with slow activation kinetics. One gain-of-function mutation causes a single amino acid substitution in S6, and the other causes a substitution in the cytoplasmic amino terminal domain. Both mutant alleles produce channels dramatically shifted in their midpoints of activation toward hyperpolarized voltages. An egl-36::gfp fusion is expressed in egg-laying muscles and in a pair of enteric muscle motor neurons. The mutant egl-36 phenotypes can thus be explained by expression in these cells of potassium channels that are inappropriately opened at hyperpolarized potentials, causing decreased excitability due to increased potassium conductance.

Animals↗
PubMed2002

Dominantly inherited, non-coding microsatellite expansion disorders.

Dominantly inherited diseases are generally caused by mutations resulting in gain of function protein alterations. However, a CTG expansion located in the 3' untranslated portion of a kinase gene was found to cause myotonic dystrophy type 1, a multisystemic dominantly inherited disorder. The recent discovery that an untranslated CCTG expansion causes the same constellation of clinical features in myotonic dystrophy type 2 (DM2), along with other recent discoveries on DM1 pathogenesis, have led to the understanding that both DM1 and DM2 mutations are pathogenic at the RNA level. These findings indicate the existence of a new category of disease wherein repeat expansions in RNA alter cellular function. Pathogenic repeat expansions in RNA may also be involved in spinocerebellar ataxia types 8, 10 and 12, and Huntington's disease-like type 2.

Genes, Dominant↗
PubMed1988

A novel dominant transformer allele of the sex-determining gene her-1 of Caenorhabditis elegans.

We have characterized a novel dominant allele of the sex-determining gene her-1 of Caenorhabditis elegans. This allele, called n695, results in the incomplete transformation of XX animals into phenotypic males. Previously characterized recessive her-1 alleles transform XO animals into phenotypic hermaphrodites. We have identified five new recessive her-1 mutations as intragenic suppressors of n695. Three of these suppressors are weak, temperature-sensitive alleles. We show that the recessive her-1 mutations are loss-of-function alleles, and that the her-1(n695) mutation results in a gain-of-function at the her-1 locus. The existence of dominant and recessive alleles that cause opposite phenotypic transformations demonstrates that the her-1 gene acts to control sexual identity in C. elegans.

Alleles↗
PubMed1996

TSH receptor and Gs-alpha gene mutations in the pathogenesis of toxic thyroid adenomas--a note of caution.

The detection of a constitutive activation of the AC cascade by TSH-R and Gs alpha mutations in a number of TTAs should not distract from the large gap in our understanding of the pathogenesis of thyroid tumors. TTAs form only a minor fraction of all thyroid nodules, and even within this small subgroup, activating mutations have been found regionally with a highly variable incidence. If activating mutations were the sole and only cause of TTAs, a homogeneous functional and morphological response of all thyrocytes would ensue. This, however, is not the case. Rather, severe disturbances of the Gs protein-AC cascade regularly occur in TTAs. Even within thyroids affected by activating TSH-R germline mutations, some cell clones proliferate at a faster rate than others, causing nodular growth with time. Moreover, not only functional, but also morphological heterogeneity very frequently evolves even in clonal adenomas. The natural heterogeneity among individual thyrocytes may account for a different functional and proliferative response among cells affected by identical mutations or any other gain-of-function event. The recent findings in toxic adenomas must be taken together with the fact that, in the large majority of all thyroid nodules, iodine metabolism is by no means enhanced, but diminished or absent and that, in this type of tumor, no consistent pattern of growth-stimulating mutational events has yet been identified. The nature, the precise temporal sequence and interaction of the genetic, cytogenetic, and environmental events that cause the very common and often autonomous nodular growth of only a few distinct cell populations within the human thyroid gland remain largely unknown.

Adenoma↗
PubMed2000

Loss of oxidation-reduction specificity in amyotrophic lateral sclerosis-associated CuZnSOD mutants.

Both transgenic mouse and cell culture models of familial amyotrophic lateral sclerosis (FALS) support a gain-of-function effect for the mutations in copper-zinc superoxide dismutase (CuZnSOD) associated with FALS, but the nature of the function gained remains incompletely characterized. We previously reported an enhanced peroxidase activity for FALS-associated CuZnSOD mutants. Because one of the targets of such activity is CuZnSOD itself, we examined peroxide-mediated inactivation of wild-type and mutant CuZnSODs, and found that the mutants are more readily inactivated. Inactivation of the mutants was associated with fragmentation, which did not occur in the wild-type enzyme under these conditions. Furthermore, the reduction of the FALS-associated mutants by ascorbate was enhanced markedly when compared to the wild-type enzyme. The visible spectra of the mutants showed a consistent blue shift of the peak at 680 nm in the wild-type enzyme, suggesting an alteration in copper-site geometry. These results extend previous studies demonstrating enhanced peroxidase activity in the mutants, and suggest that the toxic function that leads to motor neuron degeneration may result from a loss of specificity of the redox reactions catalyzed by CuZnSOD.

Amino Acid Substitution↗
PubMed2006

Alternative mutations of a positively selected residue elicit gain or loss of functionalities in enzyme evolution.

All molecular species in an organism are connected physically and functionally to other molecules. In evolving systems, it is not obvious to what extent functional properties of a protein can change to selective advantage and leave intact favorable traits previously acquired. This uncertainty has particular significance in the evolution of novel pathways for detoxication, because an organism challenged with new xenobiotics in the environment may still require biotransformation of previously encountered toxins. Positive selection has been proposed as an evolutionary mechanism for facile adaptive responses of proteins to changing conditions. Here, we show, by saturation mutagenesis, that mutations of a hypervariable residue in human glutathione transferase M2-2 can differentially change the enzyme's substrate-activity profile with alternative substrates and, furthermore, enable or disable dissimilar chemical reactions. Crystal structures demonstrate that activity with epoxides is enabled through removal of steric hindrance from a methyl group, whereas activities with an orthoquinone and a nitroso donor are maintained in the variant enzymes. Given the diversity of cellular activities in which a single protein can be engaged, the selective transmutation of functional properties has general significance in molecular evolution.

Enzyme Stability↗
PubMed2001

Ion channel variation causes epilepsies.

The discovery of genetically transmissible form of epilepsy associated with a mutation in a gene that codes for a subunit of a ligand-gated channel shined a new light in this field of neurological diseases. Because this gene (CHRNA4) codes for a neuronal nicotinic acetylcholine receptor subunit, functional studies could be designed to evaluate the alterations caused by this mutation. Since this initial observation, five mutations were identified and determination of their functional properties initiated. These experiments were extended to pairwise expression of the control and mutated allele to mimic the heterozygote human genotype. The first common functional trait identified so far, in four of these mutants, is an increased sensitivity to the acetylcholine, suggesting that these mutations may cause a gain of function. An alternative possibility that cannot be excluded is that conditions in the brain are such that these higher responding receptors may be more prone to desensitization. The importance of ionic channels as cause of epilepsies was further demonstrated with the identification of the association between the benign neonatal epilepsy and mutations in genes coding for potassium channel subunits (KCNQ2, KCNQ3). Additional evidences were brought by the identification of mutations in voltage-dependent sodium channels (SCN1A, SCN1B) in a form of generalized epilepsy with febrile seizures.

Acetylcholine↗
PubMed1996

Contribution of transcription factors to oncogenesis.

Transcription factors coordinate consitutive and inducible gene expression. They recognize and bind specific DNA sequences that are present in the regulatory regions of all genes, and thus allow transcriptional activation or repression of that given gene. Most transcription factors do not operate on their own, but form multiunit complexes consisting of homo- or heterodimers. A variety of genetic alterations observed in solid and hematologic malignancies result in gain or loss of function mutations of these molecules. As a consequence, a given transcription factor modulates its binding specificity and thus regulates the expression of a different set of target genes in the tumor cell as compared with normal cells. Alternatively, the transcription factor modulates its ability to interact with partner molecules and thus its binding specificity, its response to incoming signals or its functional activity, that is transcriptional activation or transcriptional repression of the targeted gene. Based on their functional implication in regulating gene expression and thus cellular behavior, loss or gain of function of transcription factor genes play a major role in the development or progression of tumors.

Cell Transformation, Neoplastic↗
PubMed1995

gld-1, a tumor suppressor gene required for oocyte development in Caenorhabditis elegans.

We have characterized 31 mutations in the gld-1 (defective in germline development) gene of Caenorhabditis elegans. In gld-1 (null) hermaphrodites, oogenesis is abolished and a germline tumor forms where oocyte development would normally occur. By contrast, gld-1 (null) males are unaffected. The hermaphrodite germline tumor appears to derive from germ cells that enter the meiotic pathway normally but then exit pachytene and return to the mitotic cycle. Certain gld-1 partial loss-of-function mutations also abolish oogenesis, but germ cells arrest in pachytene rather than returning to mitosis. Our results indicate that gld-1 is a tumor suppressor gene required for oocyte development. The tumorous phenotype suggests that gld-1(+) may function to negatively regulate proliferation during meiotic prophase and/or act to direct progression through meiotic prophase. We also show that gld-1(+) has an additional nonessential role in germline sex determination: promotion of hermaphrodite spermatogenesis. This function of gld-1 is inferred from a haplo-insufficient phenotype and from the properties of gain-of-function gld-1 mutations that cause alterations in the sexual identity of germ cells.

Animals↗
PubMed1994

A transmembrane domain of the putative channel subunit MEC-4 influences mechanotransduction and neurodegeneration in C. elegans.

Aberrant ion channel activity plays a causative role in several human disorders. Inappropriately regulated channel activity also appears to be the basis for neurodegeneration induced by dominant mutations of Caenorhabditis elegans mec-4 (mec-4(d)), a member of the degenerin gene family postulated to encode a subunit of a mechanosensory channel. The degenerin gene family has been defined by two C. elegans genes, mec-4 and deg-1, which can mutate to gain-of-function alleles that induce degeneration of specific groups of neurons. A related mammalian gene, rat alpha-rENaC, induces an amiloride-sensitive Na+ current when introduced to Xenopus oocytes, strongly suggesting that degenerin genes encode ion channel proteins. Deduced amino-acid sequences of the degenerins include two predicted membrane-spanning domains. Here we show that conserved amino acids within the second membrane-spanning domain (MSDII) are critical for MEC-4 activity and that specific substitutions within MSDII, whether encoded in cis or in trans to a mec-4(d) mutation, block or delay the onset of degeneration. Remarkably, MSDII from two other family members, C. elegans deg-1 and rat alpha-rENaC, can functionally substitute for MEC-4 MSDII in chimaeric proteins. Our results support a structural model for a mechanosensory channels in which multiple MEC-4 subunits are oriented such that MSDII lines the channel pore, and a neurodegeneration model in which aberrant ion flow through this channel is a key event.

Alleles↗
PubMed2000

Mutations modulating the Argos-regulated signaling pathway in Drosophila eye development.

Argos is a secreted protein that contains an EGF-like domain and acts as an inhibitor of Drosophila EGF receptor activation. To identify genes that function in the Argos-regulated signaling pathway, we performed a genetic screen for enhancers and suppressors of the eye phenotype caused by the overexpression of argos. As a result, new alleles of known genes encoding components of the EGF receptor pathway, such as Star, sprouty, bulge, and clown, were isolated. To study the role of clown in development, we examined the eye and wing phenotypes of the clown mutants in detail. In the eye discs of clown mutants, the pattern of neuronal differentiation was impaired, showing a phenotype similar to those caused by a gain-of-function EGF receptor mutation and overexpression of secreted Spitz, an activating ligand for the EGF receptor. There was also an increased number of pigment cells in the clown eyes. Epistatic analysis placed clown between argos and Ras1. In addition, we found that clown negatively regulated the development of wing veins. These results suggest that the clown gene product is important for the Argos-mediated inhibition of EGF receptor activation during the development of various tissues. In addition to the known genes, we identified six mutations of novel genes. Genetic characterization of these mutants suggested that they have distinct roles in cell differentiation and/or survival regulated by the EGF receptor pathway.

Animals↗
PubMed1998

Suppressors of position-effect variegation in Drosophila melanogaster affect expression of the heterochromatic gene light in the absence of a chromosome rearrangement.

Suppressors of position-effect variegation (Su(var)s) in Drosophila melanogaster are usually studied in the presence of chromosomal rearrangements, which exhibit variegated expression of euchromatic genes moved near to, or heterochromatic genes moved away from, centromeric heterochromatin. However, the effects of Su(var) mutations on heterochromatic gene expression in the absence of a variegating re-arrangement have not yet been defined. Here we present a number of results which suggest that Su(var) gene products can interact to affect the expression of the light gene in its normal heterochromatic location. We initially observed that eye pigment was reduced in several Su(var) double mutants; the phenotype resembled that of light mutations and was more severe when only one copy of the light gene was present. This reduced pigmentation could be alleviated by a duplication for the light gene or by a reduction in the amount of cellular heterochromatin. In addition, the viability of most Su(var) double mutant combinations tested was greatly reduced in a genetic background of reduced light gene dosage, when extra heterochromatin is present. We conclude that Su(var) gene products can affect expression of the heterochromatic light gene in the absence of any chromosomal rearrangements. However, it is noteworthy that mutations in any single Su(var) gene have little effect on light expression; we observe instead that different pairings of Su(var) mutations are required to show an effect on light expression. Interestingly, we have obtained evidence that at least two of the second chromosome Su(var) mutations are gain-of-function lesions, which also suggests that there may be different modes of interaction among these genes. It may therefore be possible to use this more sensitive assay of Su(var) effects on heterochromatic genes to infer functional relationships among the products of the 50 or more known Su(var) loci.

Animals↗
PubMed2004

Functional implications of a novel EA2 mutation in the P/Q-type calcium channel.

Episodic ataxia type 2 (EA2) is an autosomal dominant condition characterized by paroxysmal attacks of ataxia, vertigo, and nausea, typically lasting minutes to days in duration. These symptoms can be prevented or significantly attenuated by the oral administration of acetazolamide; however, the mechanism by which acetazolamide ameliorates EA2 symptoms is unknown. EA2 typically results from nonsense mutations in the CACNA1A gene that encodes the alpha1A (Cav2.1) subunit of the P/Q-type calcium (Ca2+) channel. We have identified a novel H1736L missense mutation in the CACNA1A gene associated with the EA2 phenotype. This mutation is localized near the pore-forming region of the P/Q-type Ca2+ channel. Functional analysis of P/Q-type channels containing the mutation show that the H1736L alteration affects several channel properties, including reduced current density, increased rate of inactivation, and a shift in the voltage dependence of activation to more positive values. Although these findings are consistent with an overall loss of P/Q-type channel function, the mutation also caused some biophysical changes consistent with a gain of function. We also tested the direct effect of acetazolamide on both wild-type and H1736L mutated P/Q-type channels and did not observe any direct action on channel properties of this pharmacological agent used to treat EA2 patients.

Acetazolamide↗
PubMed2002

Genetic basis of chronic pancreatitis.

BACKGROUND: Pancreatitis has a proven genetic basis in a minority of patients. METHODS: Review of the literature on genetics of pancreatitis. RESULTS: Ever since the discovery that in most patients with hereditary pancreatitis a mutation in the gene encoding for cationic trypsinogen (R122H) was found that results in a gain of trypsin function', many other mutations in the cationic trypsinogen gene, as well as in the gene encoding for pancreatic secretory trypsin inhibitor, have been found in patients with chronic pancreatitis. Furthermore, mutations in other genes, like the mucoviscoidosis-gene encoding for a chloride channel, and in genes encoding for enzymes involved in the metabolism of ethanol, have been linked to chronic pancreatitis. This article reviews the highlights that have been achieved in this field of pancreatic research. CONCLUSIONS: Recent data suggest that genetics may play a role in the pathogenesis of pancreatitis.

Chronic Disease↗