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Results for “Loss of Function Mutation”

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PubMed1993

Dominant unc-37 mutations suppress the movement defect of a homeodomain mutation in unc-4, a neural specificity gene in Caenorhabditis elegans.

The unc-4 gene of Caenorhabditis elegans encodes a homeodomain protein that defines synaptic input to ventral cord motor neurons. unc-4 mutants are unable to crawl backward because VA motor neurons are miswired with synaptic connections normally reserved for their sister cells, the VB motor neurons. These changes in connectivity are not accompanied by any visible effects upon neuronal morphology, which suggests that unc-4 regulates synaptic specificity but not axonal guidance or outgrowth. In an effort to identify other genes in the unc-4 pathway, we have devised a selection scheme for rare mutations that suppress the Unc-4 phenotype. We have isolated four, dominant, extragenic, allele-specific suppressors of unc-4(e2322ts), a temperature sensitive allele with a point mutation in the unc-4 homeodomain. Our data indicate that these suppressors are gain-of-function mutations in the previously identified unc-37 gene. We show that the loss-of-function mutation unc-37(e262) phenocopies the Unc-4 movement defect but does not prevent unc-4 expression or alter VA motor neuron morphology. These findings suggest that unc-37 functions with unc-4 to specify synaptic input to the VA motor neurons. We propose that unc-37 may be regulated by unc-4. Alternatively, unc-37 may encode a gene product that interacts with the unc-4 homeodomain.

Alleles↗

PubMed1995

Genetic and molecular characterization of a gene encoding a wide specificity purine permease of Aspergillus nidulans reveals a novel family of transporters conserved in prokaryotes and eukaryotes.

In Aspergillus nidulans, loss-of-function mutations in the uapA and azgA genes, encoding the major uric acid-xanthine and hypoxanthine-adenine-guanine permeases, respectively, result in impaired utilization of these purines as sole nitrogen sources. The residual growth of the mutant strains is due to the activity of a broad specificity purine permease. We have identified uapC, the gene coding for this third permease through the isolation of both gain-of-function and loss-of-function mutations. Uptake studies with wild-type and mutant strains confirmed the genetic analysis and showed that the UapC protein contributes 30% and 8-10% to uric acid and hypoxanthine transport rates, respectively. The uapC gene was cloned, its expression studied, its sequence and transcript map established, and the sequence of its putative product analyzed. uapC message accumulation is: (i) weakly induced by 2-thiouric acid; (ii) repressed by ammonium; (iii) dependent on functional uaY and areA regulatory gene products (mediating uric acid induction and nitrogen metabolite repression, respectively); (iv) increased by uapC gain-of-function mutations which specifically, but partially, suppress a leucine to valine mutation in the zinc finger of the protein coded by the areA gene. The putative uapC gene product is a highly hydrophobic protein of 580 amino acids (M(r) = 61,251) including 12-14 putative transmembrane segments. The UapC protein is highly similar (58% identity) to the UapA permease and significantly similar (23-34% identity) to a number of bacterial transporters. Comparisons of the sequences and hydropathy profiles of members of this novel family of transporters yield insights into their structure, functionally important residues, and possible evolutionary relationships.

Amino Acid Sequence↗

PubMed1992

Developmental arrest and ecdysteroid deficiency resulting from mutations at the dre4 locus of Drosophila.

Loss-of-function mutations of the dre4 gene of Drosophila melanogaster caused stage-specific developmental arrest, the stages of arrest coinciding with periods of ecdysteroid (molting hormone) regulated development. Nonconditional mutations resulted in the arrest of larval development in the first instar; embryogenesis was not impaired, and mutant larvae were behaviorally normal and long-lived. At 31 degrees the temperature-sensitive dre4e55 allele caused the arrest of larval development in the first or second instars. When upshifted to 31 degrees at various times during development, dre4e55 mutants exhibited nonpupariation of third-instar larvae, failure of pupal head eversion, failure of adult differentiation, or noneclosion of pharate adults. Under some temperature regimens second-instar larvae pupariated precociously without entering the normally intervening third-instar. Nonpupariation and defects in metamorphosis were associated with the reduction or elimination of ecdysteroid peaks normally associated with late-larval, prepupal, pupal and pharate adult development. Ecdysteroid production by larval ring glands from dre4e55 hemizygous larvae was suppressed after 2 hr of incubation in vitro at 31 degrees, indicating autonomous expression of the dre4 gene in the ring gland. We postulate that the dre4 gene is required for ecdysteroid production at multiple stages of Drosophila development and that the pathologies observed in dre4 mutants reflect developmental consequences of ecdysteroid deficiency.

Animals↗

PubMed1994

Characterization of Star and its interactions with sevenless and EGF receptor during photoreceptor cell development in Drosophila.

Loss-of-function mutations in Star impart a dominant rough eye phenotype and, when homozygous, are embryonic lethal with ventrolateral cuticular defects. We have cloned the Star gene and show that it encodes a novel protein with a putative transmembrane domain. Star transcript is expressed in a dynamic pattern in the embryo including in cells of the ventral midline. In the larval eye disc, Star is expressed first at the morphogenetic furrow, then in the developing R2, R5, and R8 cells as well as in the posterior clusters of the disc in additional R cells. Star interacts with Drosophila EGF receptor in the eye and mosaic analysis of Star in the larval eye disc reveals that homozygous Star patches contain no developing R cells. Taken together with the expression pattern at the morphogenetic furrow, these results demonstrate an early role for Star in photoreceptor development. Additionally, loss-of-function mutations in Star act as suppressors of R7 development in a sensitized genetic background involving the Son of sevenless (Sos) locus, and overexpression of Star enhances R7 development in this genetic background. Based on the genetic interactions with Sos, we suggest that Star also has a later role in photoreceptor development including the recruitment of the R7 cell through the sevenless pathway.

Amino Acid Sequence↗

PubMed2026

Inference of elevated mutation rates and variant effects using 700k exomes.

Genomic sequencing is now widely accessible for genetic diagnostics and is emerging as a component of newborn screening. This technological development generates the need to characterize incoming mutations, create comprehensive datasets of genes causing rare Mendelian disorders, and identify pathogenic variants. Large-scale exome sequencing datasets such as Genome Aggregation Database (gnomAD) have been assembled to help address these challenges. The recent release of gnomAD (v4; n = 730,947) uncovers millions of rare coding variants, many of which have arisen more than once by independent recurrent mutations in the rapidly growing recent human population. Here, we use newly developed theoretical understanding of sampling properties of rare variants to estimate key population genetics parameters of practical importance to human genetics such as demography history, mutation rate, and selection. Solely relying on population data, our method Population Inferred Estimates of Selection (PIES) identifies novel genes with loss-of-function mutational hotspots likely due to selection in spermatogonia. PIES efficiently estimates selection coefficients for heterozygous loss-of-function variants. Combining population genetics inference with variant effect predictors, PIES predicts pathogenic missense mutations and improves variant prioritization for genetic diagnostics and newborn screening.

Journal Article↗

PubMed2026

Disruption of major Ptchd1 isoforms causes autistic traits in social behavior and communication.

PTCHD1 is an X-linked three-exon gene associated with autism spectrum disorder (ASD) and/or intellectual disability (ID). Mice lacking Ptchd1 exon 2 (Ptchd1Δexon2) exhibit hyperactivity and learning impairments, but do not recapitulate ASD-like traits. Through mapping of clinically reported loss-of-function mutations in human patients, we determined that PTCHD1 exon 3 is a high-risk locus. We therefore generated an alternative Ptchd1 knockout mouse model by targeting Ptchd1 exon 3 (Ptchd1Δexon3) using CRISPR/Cas9. Our analyses revealed that two major PTCHD1/Ptchd1 transcripts-a (full-length) and c (shorter)-were expressed in the brain. In Ptchd1Δexon2 mice, Ptchd1_a was lost, but Ptchd1_c was compensatorily upregulated, and these mice showed no ASD-like social deficits. In Ptchd1Δexon3 mutants, both Ptchd1_a and Ptchd1_c were lost, along with dysregulation of social and communication behaviors, increased repetitive behavior, and motor and learning impairments. Our side-by-side analyses of Ptchd1Δexon2 and Ptchd1Δexon3 mice suggest a functional link between PTCHD1/Ptchd1 and ASD, demonstrating that loss-of-function mutations disrupting C-terminal Ptchd1 lead to robust ASD-relevant phenotypes in mice, more faithfully recapitulating clinically observed traits.

Animals↗

PubMed1994

The function of argos in regulating cell fate decisions during Drosophila eye and wing vein development.

The Drosophila argos gene, which encodes a secreted protein with an EGF motif, is involved in several developmental processes regulating cell-cell interactions such as eye morphogenesis. Loss-of-function mutations in the argos gene cause an increase in the number of photoreceptor cells and cone cells, impaired retinal projections to the optic lobe, and the formation of extra veins. We show here that ubiquitously expressed argos product restored all these loss-of-function phenotypes. Overexpression of argos in the wild-type background resulted in the reduced number of photoreceptor cells, cone cells, and pigment cells, which are phenotypes opposite to those of the loss-of-function mutants. The argos gene is expressed in developing wing veins. Ubiquitous argos expression caused loss of veins in a dose-dependent manner. This phenotype was enhanced by the loss-of-function rhomboid mutation, implying the possibility that argos and rhomboid play key roles in a common pathway for normal wing vein formation. We propose that argos acts as an inhibitory signal for cellular differentiation in the developing eye and wing.

Animals↗

PubMed1993

Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene.

Estrogen receptor and its ligand, estradiol, have long been thought to be essential for survival, fertility, and female sexual differentiation and development. Consistent with this proposed crucial role, no human estrogen receptor gene mutations are known, unlike the androgen receptor, where many loss of function mutations have been found. We have generated mutant mice lacking responsiveness to estradiol by disrupting the estrogen receptor gene by gene targeting. Both male and female animals survive to adulthood with normal gross external phenotypes. Females are infertile; males have a decreased fertility. Females have hypoplastic uteri and hyperemic ovaries with no detectable corpora lutea. In adult wild-type and heterozygous females, 3-day estradiol treatment at 40 micrograms/kg stimulates a 3- to 4-fold increase in uterine wet weight and alters vaginal cornification, but the uteri and vagina do not respond in the animals with the estrogen receptor gene disruption. Prenatal male and female reproductive tract development can therefore occur in the absence of estradiol receptor-mediated responsiveness.

Animals↗

PubMed1992

The segmentation gene runt is needed to activate Sex-lethal, a gene that controls sex determination and dosage compensation in Drosophila.

In Drosophila, sex is determined by the relative number of X chromosomes to autosomal sets (X:A ratio). The amount of products from several X-linked genes, called sisterless elements, is used to indicate to Sex-lethal the relative number of X chromosomes present in the cell. In response to the X:A signal, Sex-lethal is activated in females but remains inactive in males, being responsible for the control of both sex determination and dosage compensation. Here we find that the X-linked segmentation gene runt plays a role in this process. Reduced function of runt results in female-specific lethality and sexual transformation of XX animals that are heterozygous for Sxl or sis loss-of-function mutations. These interactions are suppressed by SxlM1, a mutation that constitutively expresses female Sex-lethal functions, and occur at the time when the X:A signal determines Sex-lethal activity. Moreover, the presence of a loss-of-function runt mutation masculinizes triploid intersexes. On the other hand, runt duplications cause a reduction in male viability by ectopic activation of Sex-lethal. We conclude that runt is needed for the initial step of Sex-lethal activation, but does not have a major role as an X-counting element.

Animals↗

PubMed1991

Molecular characterization of the trithorax gene, a positive regulator of homeotic gene expression in Drosophila.

The Drosophila gene trithorax (trx) is required for the normal expression of a number of the homeotic genes in the bithorax complex (BX-C) and the Antennapedia complex (ANT-C). Flies homozygous for trx mutations exhibit segmental identity transformations similar to those caused by loss-of-function mutations in the homeotic genes Sex combs reduced (Scr), Ultrabithorax (Ubx), abdominal-A (abd-A), and Abdominal-B (Abd-B). We present a molecular characterization of the trx locus and show that it is necessary for normal levels of Antennapedia (Antp), Ubx, and abd-A protein accumulation. Interestingly, the loss of trx function differentially affects the expression these proteins; Ubx protein levels are greatly reduced, abd-A protein levels are reduced to a lesser extent, and Antp protein levels are only slightly reduced. P-element mediated transformation using 34 kb of genomic DNA containing the 25 kb trx transcription unit identifies all sequences necessary for normal trx function and limits the 5' and 3' flanking sequences that could be used in a regulatory capacity to relatively small regions. The primary transcription unit is differentially spliced to produce two large transcripts of 12 and 15 kb that have different developmental profiles.

Animals↗

PubMed1995

A new PAX6 mutation in familial aniridia.

Aniridia (lack of iris) is caused by loss of function mutations in one copy of the PAX6 gene. Here we present a new PAX6 splice mutation in a family with autosomal dominant aniridia. The mutation is a single nucleotide change which, although occurring within an exon, affects the splice junction consensus and results in skipping of that exon.

Aniridia↗

PubMed1994

Molecular analysis of the Drosophila EGF receptor homolog reveals that several genetically defined classes of alleles cluster in subdomains of the receptor protein.

Mutations in the torpedo gene, which encodes the fruitfly homolog of the epidermal growth factor receptor (DER), disrupt a variety of developmental processes in Drosophila. These include the survival of certain embryonic ectodermal tissues, the proliferation of the imaginal discs, the morphogenesis of several adult ectodermal structures and oogenesis, torpedo is genetically complex: a number of alleles of the gene differentially affect the development of specific tissues, such as the eye, wing, bristles and ovary. In addition, torpedo mutations exhibit interallelic complementation. Molecular analysis of 24 loss-of-function mutations in the torpedo gene provides insights into the mechanistic basis of its genetic complexity. We observe an intriguing correlation between molecular lesions and mutant phenotypes. Alleles that differentially affect specific developmental processes encode receptors with altered extracellular domains. Alleles that fully or partially complement a wide range of embryonic and postembryonic torpedo mutations encode receptors with altered intracellular domains. From these findings we conclude the following. First, the torpedo protein may be activated by tissue-specific ligands. Second, the torpedo receptor tyrosine kinase may phosphorylate multiple substrates. Third, signal transduction by torpedo appears to require the physical association of receptors. Finally, the extracellular domain of the Torpedo protein may play an essential role in mediating receptor-receptor interactions.

Alleles↗

PubMed1990

Transvection in the Drosophila Ultrabithorax gene: a Cbx1 mutant allele induces ectopic expression of a normal allele in trans.

In wild-type Drosophila melanogaster larvae, the Ultrabithorax (Ubx) gene is expressed in the haltere imaginal discs but not in the majority of cells of the wing imaginal discs. Ectopic expression of the Ubx gene in wing discs can be elicited by the presence of Contrabithorax (Cbx) gain-of-function alleles of the Ubx gene or by loss-of-function mutations in Polycomb (Pc) or in other trans-regulatory genes which behave as repressors of Ubx gene activity. Several Ubx loss-of-function alleles cause the absence of detectable Ubx proteins (UBX) or the presence of truncated UBX lacking the homeodomain. We have compared adult wing phenotypes with larval wing disc UBX patterns in genotypes involving double mutant chromosomes carrying in cis one of those Ubx mutations and the Cbx1 mutation. We show that such double mutant genes are (1) active in the same cells in which the single mutant Cbx1 is expressed, although they are unable to yield functional proteins, and (2) able to induce ectopic expression of a normal homologous Ubx allele in a part of the cells in which the single mutant Cbx1 is active. That induction is conditional upon pairing of the homologous chromosomes (the phenomenon known as transvection), and it is not mediated by UBX. Depletion of Pc gene products by Pc3 mutation strongly enhances the induction phenomenon, as shown by (1) the increase of the number of wing disc cells in which induction of the homologous allele is detectable, and (2) the induction of not only a paired normal allele but also an unpaired one.

Alleles↗

PubMed2025

Quinoxaline-based anti-schistosomal compounds have potent anti-plasmodial activity.

The human pathogens Plasmodium and Schistosoma are each responsible for over 200 million infections annually, especially in low- and middle-income countries. There is a pressing need for new drug targets for these diseases, driven by emergence of drug-resistance in Plasmodium and an overall dearth of drug targets against Schistosoma. Here, we explored the opportunity for pathogen-hopping by evaluating a series of quinoxaline-based anti-schistosomal compounds for their activity against P. falciparum. We identified compounds with low nanomolar potency against 3D7 and multidrug-resistant strains. In vitro resistance selections using wildtype and mutator P. falciparum lines revealed a low propensity for resistance. Only one of the series, compound 22, yielded resistance mutations, including point mutations in a non-essential putative hydrolase pfqrp1, as well as copy number amplification of a phospholipid-translocating ATPase, pfatp2, a potential target. Notably, independently generated CRISPR-edited mutants in pfqrp1 also showed resistance to compound 22 and a related analogue. Moreover, previous lines with pfatp2 copy number variations were similarly less susceptible to challenge with the new compounds. Finally, we examined whether the predicted hydrolase activity of PfQRP1 underlies its mechanism of resistance, showing that both mutation of the putative catalytic triad and a more severe loss of function mutation elicited resistance. Collectively, we describe a compound series with potent activity against two important pathogens and their potential target in P. falciparum.

Quinoxalines↗

PubMed1995

Loss of function effect of RET mutations causing Hirschsprung disease.

We have introduced three Hirschsprung (HSCR) mutations localized in the tyrosine kinase domain of RET into the RET/PTC2 chimaeric oncogene which is capable of transforming NIH3T3 mouse fibroblasts and of differentiating pC12 rat pheochromocytoma cells. The three HSCR mutations abolished the biological activity of RET/PTC2 in both cell types and significantly decreased its tyrosine phosphorylation. By contrast, a rare polymorphism in exon 18 does not alter the transforming capability of RET/PTC2 or its tyrosine phosphorylation. These data suggest a loss of function effect of HSCR mutations which might act through a dominant negative mechanism. Our model system is therefore capable of discriminating between causative HSCR mutations and rare polymorphisms in the tyrosine kinase domain of RET.

3T3 Cells↗

PubMed1990

Tumor suppressor genes.

The retinoblastoma sensitivity protein (Rb) and the p53 gene product both appear to function as negative regulators of cell division or abnormal cellular growth in some differentiated cell types. Several types of cancers have been shown to be derived from cells that have extensively mutated both alleles of one or both of these genes, resulting in a loss-of-function mutation. In the case of the p53 gene, this mutational process appears to occur in two steps, with the first mutation at the p53 locus resulting in a trans-dominant phenotype. The mutant p53 gene product enters into an oligomeric protein complex with the wild-type p53 protein derived from the other normal allele and such a complex is inactive or less efficient in its negative regulation of growth control. This intermediate stage of carcinogenesis selects for the proliferation of cells with one mutant allele, enhancing the probability of obtaining a cancer cell with both alleles damaged. The DNA tumor viruses have evolved mechanisms to interact with the Rb and p53 negative regulators of cellular growth in order to enhance their own replication in growing cells. SV40 and adenovirus type 5 produce viral encoded proteins that also form oligomeric protein complexes with p53 and Rb, presumably inactivating their functions. These viral proteins are also the oncogene products of these viruses. Thus, the mechanisms by which cancer may arise in a host, via mutations or virus infections, have fundamental common pathways effecting the same cellular genes and gene products; Rb and p53.

Amino Acid Sequence↗

PubMed1992

Meiotic spindle assembly in Drosophila females: behavior of nonexchange chromosomes and the effects of mutations in the nod kinesin-like protein.

Mature Drosophila oocytes are arrested in metaphase of the first meiotic division. We have examined microtubule and chromatin reorganization as the meiosis I spindle assembles on maturation using indirect immunofluorescence and laser scanning confocal microscopy. The results suggest that chromatin captures or nucleates microtubules, and that these subsequently form a highly tapered spindle in which the majority of microtubules do not terminate at the poles. Nonexchange homologs separate from each other and move toward opposite poles during spindle assembly. By the time of metaphase arrest, these chromosomes are positioned on opposite half spindles, between the metaphase plate and the spindle poles, with the large nonexchange X chromosomes always closer to the metaphase plate than the smaller nonexchange fourth chromosomes. Nonexchange homologs are therefore oriented on the spindle in the absence of a direct physical linkage, and the spindle position of these chromosomes appears to be determined by size. Loss-of-function mutations at the nod locus, which encodes a kinesin-like protein, cause meiotic loss and nondisjunction of nonexchange chromosomes, but have little or no effect on exchange chromosome segregation. In oocytes lacking functional nod protein, most of the nonexchange chromosomes are ejected from the main chromosomal mass shortly after the nuclear envelope breaks down and microtubules interact with the chromatin. In addition, the nonexchange chromosomes that are associated with spindles in nod/nod oocytes show excessive poleward migration. Based on these observations, and the structural similarity of the nod protein and kinesin, we propose that nonexchange chromosomes are maintained on the half spindle by opposing poleward and anti-poleward forces, and that the nod protein provides the anti-poleward force.

Animals↗

PubMed1989

Genetic analysis of the homeotic gene complex (HOM-C) in the beetle Tribolium castaneum.

Our laboratories have undertaken both genetic and molecular studies of the homeotic gene complex (HOM-C) of the beetle Tribolium castaneum, and this paper discusses results from our genetic analyses. We describe here the adult phenotypes and complementation behavior of over 50 new mutations. Many of these homeotic phenotypes resemble those of Drosophila melanogaster, but few precisely parallel the segmental transformations seen in this fly. Analysis of putative loss-of-function mutations affecting the head and thorax suggests that the maxillopedia and Cephalothorax genes most closely resemble proboscipedia and Sex combs reduced of Drosophila. In the abdomen, putative loss-of-function alleles of Abdominal affect a domain corresponding to those of the combined abdominal-A and Abdominal-B genes of Drosophila. In contrast to the situation in flies, Abdominal loss-of-function variants in Tribolium cause anteriorward transformations in A3-A5a, but posteriorward transformations in A5p-A7. The implications of the differences in developmental strategies evolved in Tribolium vs Drosophila are discussed.

Abdomen↗