scholarly journals Loss-of-function in IRF2BPL is associated with neurological phenotypes

2018 ◽  
Author(s):  
Paul C. Marcogliese ◽  
Vandana Shashi ◽  
Rebecca C. Spillmann ◽  
Nicholas Stong ◽  
Jill A. Rosenfeld ◽  
...  
Keyword(s):  
Nervous System ◽  
Population Genomics ◽  
Stop Codon ◽  
Ectopic Expression ◽  
Premature Stop Codon ◽  
Model Organism ◽  
Global Developmental Delay ◽  
Mendelian Disease ◽  
Loss Of Function ◽  
Missense Variants

AbstractThe Interferon Regulatory Factor 2 Binding Protein Like (IRF2BPL) gene encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Here we describe seven individuals affected with neurological symptoms who carry damaging heterozygous variants in IRF2BPL. Five cases carrying nonsense variants in IRF2BPL resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. Two additional individuals, both with missense variants, display global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles. The bioinformatics signature for IRF2BPL based on population genomics is consistent with a gene that is intolerant to variation. We show that the IRF2BPL ortholog in the fruit fly, called pits (protein interacting with Ttk69 and Sin3A), is broadly expressed including the nervous system. Complete loss of pits is lethal early in development, whereas partial knock-down with RNA interference in neurons leads to neurodegeneration, revealing requirement for this gene in proper neuronal function and maintenance. The nonsense variants in IRF2BPL identified in patients behave as severe loss-of-function alleles in this model organism, while ectopic expression of the missense variants leads to a range of phenotypes. Taken together, IRF2BPL and pits are required in the nervous system in humans and flies, and their loss leads to a range of neurological phenotypes in both species.

scholarly journals SUN-085 Clinical and Hormonal Features of 37 Families with Central Precocious Puberty Due to MKRN3 Loss-Of -Function Mutations

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Carlos Eduardo Seraphim ◽  
Ana Pinheiro Machado Canton ◽  
Luciana Ribeiro Montenegro ◽  
Maiara Ribeiro Piovesan ◽  
Tabata Mariz Bohlen ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Central Precocious Puberty ◽  
Time Interval ◽  
Mrna Levels ◽  
Loss Of Function ◽  
Missense Variants ◽  
Amino Terminal ◽  
Mediterranean Countries

Abstract Context: Loss-of-function mutations in the maternally imprinted Makorin RING-finger 3 (MKRN3) gene (15q11.2) are the most prevalent cause of familial central precocious puberty (CPP). Objectives: To analyze the phenotypes of a large cohort of children with CPP due to MKRN3 mutations and to compare them with the phenotypes of idiopathic CPP. Setting and Participants: We studied 73 individuals from 37 families with mutations in MKRN3 originating from nine different countries. The phenotypes of these patients at initial diagnosis were compared to a cohort of 124 patients with idiopathic CPP. Additionally, expression of nine different genes implicated with pubertal timing, including MKRN3, was performed in the hypothalamus of female mice in different phases of sexual maturation. Results: Nineteen different heterozygous, paternally inherited mutations in MKRN3 were identified in 73 patients with CPP (48 girls and 25 boys). Six MKRN3 mutations were frameshifts, one introduced a premature stop codon, 11 were missense mutations predicted to be pathogenic, and one was a deletion in the promoter region. A frameshift mutation affecting codon 161 in the amino terminal region of the protein was the most frequent MKRN3 defect (46%), representing a hotspot region. Among the cohort with MKRN3 mutations, first pubertal signs occurred at 6·2 ± 1·2 years in girls and 7·6 ± 1·4 years in boys. Patients harboring severe frameshift/nonsense mutations did not differ significantly in any clinical or hormonal parameters compared to the 20 patients with missense variants. However, when the 48 girls with MKRN3 mutations were compared with 124 idiopathic CPP girls, some parameters could be considered as possible predictors of the genetic cause: a lower age at first medical appointment (7·1 ± 1·1 in the MKRN3 group vs. 8·0 ± 2 years in the idiopathic group; p< 0.001) and a shorter time interval between puberty onset and medical assistance (0·8 ± 0·8 vs 2·2 ± 2·1 years; p< 0.001). Interestingly, the other predictor of MKRN3 mutations was a higher basal FSH level (5·1 ± 2·3 vs 3·9 ± 2·7 IU/L; p = 0.017) at first evaluation, although no cutoff value yielded good accuracy. Patients originating from European/Mediterranean countries were more likely to have missense variants (56% of all mutations) than North American and South American (23%) counterparts (p <0.001). Mouse Mkrn3 mRNA levels in the arcuate nucleus were highest in the prepubertal phase when compared with expression of other genes and Mkrn3 decreased progressively through puberty and adult ages. Conclusions: Different types of loss-of-function MKRN3 mutations were associated with premature sexual development in both sexes. Their phenotypes were relatively uniform, regardless of the mutation type. Clinical features of children with MKRN3 mutations were similar to the idiopathic CPP group.

scholarly journals Cis-Segregation of c.1171C>T Stop Codon (p.R391*) in SERPINC1 Gene and c.1691G>A Transition (p.R506Q) in F5 Gene and Selected GWAS Multilocus Approach in Inherited Thrombophilia

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 934
Author(s):  
Donato Gemmati ◽  
Giovanna Longo ◽  
Eugenia Franchini ◽  
Juliana Araujo Silva ◽  
Ines Gallo ◽  
...  
Keyword(s):  
At Risk ◽  
Stop Codon ◽  
Association Studies ◽  
Premature Stop Codon ◽  
Large Family ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Gene Markers ◽  
Inherited Thrombophilia ◽  
Fv Leiden

Inherited thrombophilia (e.g., venous thromboembolism, VTE) is due to rare loss-of-function mutations in anticoagulant factors genes (i.e., SERPINC1, PROC, PROS1), common gain-of-function mutations in procoagulant factors genes (i.e., F5, F2), and acquired risk conditions. Genome Wide Association Studies (GWAS) recently recognized several genes associated with VTE though gene defects may unpredictably remain asymptomatic, so calculating the individual genetic predisposition is a challenging task. We investigated a large family with severe, recurrent, early-onset VTE in which two sisters experienced VTE during pregnancies characterized by a perinatal in-utero thrombosis in the newborn and a life-saving pregnancy-interruption because of massive VTE, respectively. A nonsense mutation (CGA > TGA) generating a premature stop-codon (c.1171C>T; p.R391*) in the exon 6 of SERPINC1 gene (1q25.1) causing Antithrombin (AT) deficiency and the common missense mutation (c.1691G>A; p.R506Q) in the exon 10 of F5 gene (1q24.2) (i.e., FV Leiden; rs6025) were coinherited in all the symptomatic members investigated suspecting a cis-segregation further confirmed by STR-linkage-analyses [i.e., SERPINC1 IVS5 (ATT)5–18, F5 IVS2 (AT)6–33 and F5 IVS11 (GT)12–16] and SERPINC1 intragenic variants (i.e., rs5878 and rs677). A multilocus investigation of blood-coagulation balance genes detected the coexistence of FV Leiden (rs6025) in trans with FV HR2-haplotype (p.H1299R; rs1800595) in the aborted fetus, and F11 rs2289252, F12 rs1801020, F13A1 rs5985, and KNG1 rs710446 in the newborn and other members. Common selected gene variants may strongly synergize with less common mutations tuning potential life-threatening conditions when combined with rare severest mutations. Merging classic and newly GWAS-identified gene markers in at risk families is mandatory for VTE risk estimation in the clinical practice, avoiding partial risk score evaluation in unrecognized at risk patients.

scholarly journals Partitioning of N-Ethylmaleimide-Sensitive Fusion (NSF) Protein Function in Drosophila melanogaster: dNSF1 Is Required in the Nervous System, and dNSF2 Is Required in Mesoderm

Genetics ◽  
2001 ◽  
Vol 158 (1) ◽  
pp. 265-278
Author(s):  
Jessica A Golby ◽  
Leigh Anna Tolar ◽  
Leo Pallanck
Keyword(s):  
Nervous System ◽  
Protein Function ◽  
Ectopic Expression ◽  
Drosophila Genome ◽  
Loss Of Function ◽  
Stage Of Development ◽  
Expression Studies ◽  
Larval Nervous System ◽  
Constitutive Secretion ◽  
Temporal And Spatial

Abstract The N-ethylmaleimide-sensitive fusion protein (NSF) promotes the fusion of secretory vesicles with target membranes in both regulated and constitutive secretion. While it is thought that a single NSF may perform this function in many eukaryotes, previous work has shown that the Drosophila genome contains two distinct NSF genes, dNSF1 and dNSF2, raising the possibility that each plays a specific secretory role. To explore this possibility, we generated mutations in the dNSF2 gene and used these and novel dNSF1 loss-of-function mutations to analyze the temporal and spatial requirements and the degree of functional redundancy between dNSF1 and dNSF2. Results of this analysis indicate that dNSF1 function is required in the nervous system beginning at the adult stage of development and that dNSF2 function is required in mesoderm beginning at the first instar larval stage of development. Additional evidence suggests that dNSF1 and dNSF2 may play redundant roles during embryonic development and in the larval nervous system. Ectopic expression studies demonstrate that the dNSF1 and dNSF2 gene products can functionally substitute for one another. These results indicate that the Drosophila NSF proteins exhibit similar functional properties, but have evolved distinct tissue-specific roles.

scholarly journals A novel Dbl family RhoGEF promotes Rho-dependent axon attraction to the central nervous system midline in Drosophila and overcomes Robo repulsion

2001 ◽  
Vol 155 (7) ◽  
pp. 1117-1122 ◽  
Author(s):  
Greg J. Bashaw ◽  
Hailan Hu ◽  
Catherine D. Nobes ◽  
Corey S. Goodman
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Rho Gtpases ◽  
Ectopic Expression ◽  
Nucleotide Exchange ◽  
Loss Of Function ◽  
Guanine Nucleotide Exchange ◽  
Positive Regulators ◽  
The Central Nervous System ◽  
Rho Gef

The key role of the Rho family GTPases Rac, Rho, and CDC42 in regulating the actin cytoskeleton is well established (Hall, A. 1998. Science. 279:509–514). Increasing evidence suggests that the Rho GTPases and their upstream positive regulators, guanine nucleotide exchange factors (GEFs), also play important roles in the control of growth cone guidance in the developing nervous system (Luo, L. 2000. Nat. Rev. Neurosci. 1:173–180; Dickson, B.J. 2001. Curr. Opin. Neurobiol. 11:103–110). Here, we present the identification and molecular characterization of a novel Dbl family Rho GEF, GEF64C, that promotes axon attraction to the central nervous system midline in the embryonic Drosophila nervous system. In sensitized genetic backgrounds, loss of GEF64C function causes a phenotype where too few axons cross the midline. In contrast, ectopic expression of GEF64C throughout the nervous system results in a phenotype in which far too many axons cross the midline, a phenotype reminiscent of loss of function mutations in the Roundabout (Robo) repulsive guidance receptor. Genetic analysis indicates that GEF64C expression can in fact overcome Robo repulsion. Surprisingly, evidence from genetic, biochemical, and cell culture experiments suggests that the promotion of axon attraction by GEF64C is dependent on the activation of Rho, but not Rac or Cdc42.

scholarly journals Synergistic Activation of Defense Responses in Arabidopsis by Simultaneous Loss of the GSL5 Callose Synthase and the EDR1 Protein Kinase

2010 ◽  
Vol 23 (5) ◽  
pp. 578-584 ◽  
Author(s):  
Anna Wawrzynska ◽  
Natalie L. Rodibaugh ◽  
Roger W. Innes
Keyword(s):  
Powdery Mildew ◽  
Positional Cloning ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Defense Responses ◽  
Loss Of Function ◽  
Callose Synthase ◽  
Synergistic Activation ◽  
Golovinomyces Cichoracearum ◽  
Inducible Gene

Loss-of-function mutations in the EDR1 gene of Arabidopsis confer enhanced resistance to Golovinomyces cichoracearum (powdery mildew). Disease resistance mediated by the edr1 mutation is dependent on an intact salicylic acid (SA) signaling pathway, but edr1 mutant plants do not constitutively express the SA-inducible gene PR-1 and are not dwarfed. To identify other components of the EDR1 signaling network, we screened for mutations that enhanced the edr1 mutant phenotype. Here, we describe an enhancer of edr1 mutant, eed3, which forms spontaneous lesions in the absence of pathogen infection, constitutively expresses both SA- and methyl jasmonate (JA)–inducible defense genes, and is dwarfed. Positional cloning of eed3 revealed that the mutation causes a premature stop codon in GLUCAN SYNTHASE-LIKE 5 (GSL5, also known as POWDERY MILDEW RESISTANT 4), which encodes a callose synthase required for pathogen-induced callose production. Significantly, gsl5 single mutants do not constitutively express PR-1 or AtERF1 (a JA-inducible gene) and are not dwarfed. Thus, loss of both EDR1 and GSL5 function has a synergistic effect. Our data suggest that EDR1 and GSL5 negatively regulate SA and JA production or signaling by independent mechanisms and that negative regulation of defense signaling by GSL5 may be independent of callose production.

scholarly journals Molecular genetic study in two patients with congenital hypoaldosteronism (types I and II) in relation to previously published hormonal studies

1998 ◽  
pp. 96-100 ◽  
Author(s):  
M Peter ◽  
K Bunger ◽  
SL Drop ◽  
WG Sippell
Keyword(s):  
Genetic Study ◽  
Stop Codon ◽  
Molecular Genetic ◽  
Premature Stop Codon ◽  
Type I ◽  
Type Ii ◽  
Loss Of Function ◽  
Molecular Genetic Study ◽  
Base Exchange ◽  
Deficiency Type

We performed a molecular genetic study in two patients with congenital hypoaldosteronism. An original study of these patients was published in this Journal in 1982. Both index cases, a girl (patient 1) and a boy (patient 2). presented with salt-wasting and failure to thrive in the neonatal period. Parents of patient 1 were not related, whereas the parents of patient 2 were cousins. Endocrine studies had shown a defect in 18-oxidation of 18-OH-corticosterone in patient 1 and a defect in the 18-hydroxylation of corticosterone in patient 2. Plasma aldosterone was decreased in both patients, whereas 18-OH-corticosterone was elevated in patient 1 and decreased in patient 2. Plasma corticosterone and 11-deoxycorticosterone were elevated in both patients, whereas cortisol and its precursors were in the normal range. According to the nomenclature proposed by Ulick, the defects are termed corticosterone methyl oxidase (CMO) deficiency type II in patient 1, and type I in patient 2 respectively. Genetic defects in the gene CYP11B2 encoding aldosterone synthase have been described in a few cases. In patient 1, we identified only one heterozygous amino acid substitution (V386A) in exon 7, which has no deleterious effect on the enzyme activity. In patient 2 and his older brother, we identified a homozygous single base exchange (G to T) in codon 255 (GAG), causing a premature stop codon E255X (TAG). The mutant enzyme has lost the five terminal exons containing the haem binding site, and is thus a loss of function enzyme. This is only the second report of a patient with CMO deficiency type II without a mutation in the exons and exon-intron boundaries, whereas the biochemical phenotype of the two brothers with CMO deficiency type I can be explained by the patient's genotype.

scholarly journals Therapeutic base and prime editing of COL7A1 mutations in recessive dystrophic epidermolysis bullosa

2021 ◽  
Author(s):  
Sung-ah Hong ◽  
Song-Ee Kim ◽  
A-young Lee ◽  
Gue-ho Hwang ◽  
Jong Hoon Kim ◽  
...  
Keyword(s):  
Epidermolysis Bullosa ◽  
Ex Vivo ◽  
Stop Codon ◽  
Point Mutations ◽  
Premature Stop Codon ◽  
Loss Of Function ◽  
Dystrophic Epidermolysis Bullosa ◽  
Immunodeficient Mice ◽  
Type Vii Collagen ◽  
Recessive Dystrophic Epidermolysis Bullosa

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin fragility disorder caused by loss-of-function mutations in the COL7A1 gene, which encodes type VII collagen (C7), a protein that functions in skin adherence. From 36 Korean RDEB patients, we identified a total of 69 pathogenic mutations (40 variants without recurrence), including point mutations (72.5%) and insertion/deletion mutations (27.5%). We used base and prime editing to correct mutations in fibroblasts from two patients (Pat1, who carried a c.3631C>T mutation in one allele, and Pat2, who carried a c.2005C>T mutation in one allele). We applied adenine base editors (ABEs) to correct the pathogenic mutation or to bypass a premature stop codon in Pat1-derived primary fibroblasts. To expand the targeting scope, we also utilized prime editors (PEs) to correct the mutations in Pat1- and Pat2-derived fibroblasts. Ultimately, we found that both ABE- and PE-mediated correction of COL7A1 mutations restored full-length C7 expression, reversed the impaired adhesion and proliferation exhibited by the patient-derived fibroblasts, and, following transfer of edited patient-derived fibroblasts into the skin of immunodeficient mice, led to C7 deposition within the dermal-epidermal junction. These results suggest that base and prime editing could be feasible strategies for ex vivo gene editing to treat RDEB.

scholarly journals Molecular structure of soybean E-genes and their functional mutations

2020 ◽  
pp. 3-13
Author(s):  
O. Okhrymovych ◽  
◽  
S. Chebotar ◽  
G. Chebotar ◽  
D. Zharikova ◽  
...  
Keyword(s):  
Molecular Structure ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Genetic Network ◽  
Structural Features ◽  
Loss Of Function ◽  
Nucleotide Substitutions ◽  
Early Maturity ◽  
E Gene ◽  
Wide Range

In this review, we discuss features of the molecular structure of known E-loci (early maturity) and their involvement in signaling to plant flowering, depending on the sensitivity of soybean genotypes to the photoperiod. These loci contribute to the adaptation of plants to a wide range of natural conditions due to mutations in genes and QTL that control flowering time. At the molecular level, E-genes are significantly different in structural features, origin and function. The lenghth of the identified genes range from one exon to 525 bp encoding the transcription factor (E1), up to 14 exons and about 20 kb for the GmGIa gene (E2). Among the functional mutations that in most cases lead to partial or complete loss of function, there are single-nucleotide substitutions or deletions, insertions of transposon-like sequences that can lead to amino acid substitutions in the protein, shift of the reading frame, appearance of the premature stop-codon. E-gene products are receptors of signals coming from the environment and they participate in signaling pathways that control the photoperiod. The overall impact and interactions between E-genes have not been fully studied yet, the molecular structure was investigated only for E1-E4, for which a genetic network of interactions was proposed, while at the same time five loci (E6-E9 and E11) were only mapped on soybean chromosomes, and the existence of a separate E5 locus has not yet been established. In eight of the 11 E-loci, the dominant allele causes late flowering. Also there is a pleiotropic effect of E-gene alleles on yield, plant height, stress resistance, and response to low temperatures. Knowledge of the allelic state of only some of the 11 genes is not sufficient. A comprehensive understanding of the functioning of the photoperiodic genetic response network is needed. E-genes are genetic determinants that can be used during selection and creation of new varieties with programmed rates of development.

scholarly journals Lack of FAM20A, Ectopic Gingival Mineralization and Chondro/Osteogenic Modifications in Enamel Renal Syndrome

2020 ◽  
Vol 8 ◽  
Author(s):  
Victor Simancas Escorcia ◽  
Abdoulaziz Diarra ◽  
Adrien Naveau ◽  
Arnaud Dessombz ◽  
Rufino Felizardo ◽  
...  
Keyword(s):  
Stop Codon ◽  
Sequence Similarity ◽  
Premature Stop Codon ◽  
Matrix Composition ◽  
Gingival Tissue ◽  
Thoracic Vertebrae ◽  
Gingival Fibroblasts ◽  
Loss Of Function ◽  
Fiber Network ◽  
Gingival Overgrowth

Enamel renal syndrome (ERS) is a rare recessive disorder caused by loss-of-function mutations in FAM20A (family with sequence similarity 20 member A, OMIM #611062). Enamel renal syndrome is characterized by amelogenesis imperfecta, delayed or failed tooth eruption, intrapulpal calcifications, gingival overgrowth and nephrocalcinosis. Although gingival overgrowth has consistently been associated with heterotopic calcifications the pathogenesis, structure and interactions of the mineral deposits with the surrounding connective tissue are largely unknown. We here report a novel FAM20A mutation in exon 1 (c.358C > T) introducing a premature stop codon (p.Gln120*) and resulting in a complete loss of FAM20A. In addition to the typical oral findings and nephrocalcinosis, ectopic calcified nodules were also seen in the cervical and thoracic vertebrae regions. Histopathologic analysis of the gingiva showed an enlarged papillary layer associated with aberrant angiogenesis and a lamina propria displaying significant changes in its extracellular matrix composition, including disruption of the collagen I fiber network. Ectopic calcifications were found throughout the connective gingival tissue. Immunomorphological and ultrastructural analyses indicated that the calcification process was associated with epithelial degeneration and transformation of the gingival fibroblasts to chondro/osteoblastic-like cells. Mutant gingival fibroblasts cultures were prone to calcify and abnormally expressed osteoblastic markers such as RUNX2 or PERIOSTIN. Our findings expand the previously reported phenotypes and highlight some aspects of ERS pathogenesis.

Functional differences between Ultrabithorax protein isoforms in Drosophila melanogaster: evidence from elimination, substitution and ectopic expression of specific isoforms.

Genetics ◽  
1994 ◽  
Vol 136 (3) ◽  
pp. 979-991 ◽  
Author(s):  
V Subramaniam ◽  
H M Bomze ◽  
A J López
Keyword(s):  
Nervous System ◽  
Drosophila Melanogaster ◽  
Peripheral Nervous System ◽  
Mutant Allele ◽  
Stop Codon ◽  
Functional Limitation ◽  
Ectopic Expression ◽  
Protein Isoforms ◽  
Homeodomain Protein ◽  
Alternatively Spliced

Abstract The homeotic selector gene Ultrabithorax (Ubx) specifies regional identities in multiple tissues within the thorax and abdomen of Drosophila melanogaster. Ubx encodes a family of six developmentally specific homeodomain protein isoforms translated from alternatively spliced mRNAs. The mutant allele Ubx195 contains a stop codon in exon mII, one of three differential elements, and consequently produces functional UBX protein only from mRNAs of type IVa and IVb, which are expressed mainly in the central nervous system. Although it retains activity for other processes, Ubx195 behaves like a null allele with respect to development of the peripheral nervous system, indicating that UBX-IVa and IVb alone do not contribute detectable Ubx function for this tissue. The mutant allele UbxMX17 contains an inversion of exon mII. We find that this allele only produces mRNAs of type IVa, but the expression pattern of the resulting UBX-IVa protein is indistinguishable from that of total UBX protein expression in wild-type embryos. The phenotype of homozygous UbxMX17 embryos indicates that UBX-IVa cannot substitute functionally for other isoforms to promote normal development of the peripheral nervous system. This functional limitation is confirmed by a detailed analysis of the peripheral nervous system in embryos that express specific UBX isoforms ectopically under control of a heat shock promoter. Additional observations suggest that UBX isoforms also differ in their ability to function in other tissues.

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