New mutations in SERPING1 gene of Brazilian patients with hereditary angioedema

2016 ◽  
Vol 397 (4) ◽  
pp. 337-344 ◽  
Author(s):  
Nathália Cagini ◽  
C.L. Veronez ◽  
R.N. Constantino-Silva ◽  
Márcia Buzolin ◽  
Renan Paulo Martin ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Genetic Analysis ◽  
Hereditary Angioedema ◽  
Autosomal Dominant ◽  
Missense Mutations ◽  
Inherited Disease ◽  
Coding Region ◽  
Serping1 Gene ◽  
Brazilian Cohort ◽  
New Mutations

Abstract Hereditary Angioedema is an autosomal dominant inherited disease leading to oedema attacks with variable severity and localization predominantly caused by C1-INH deficit. More than 400 mutations have been already identified, however no genetic analysis of a Brazilian cohort of HAE patients with C1-INH deficiency has been published. Our aim was to perform genetic analysis of C1-INH gene (SERPING1) in Brazilian HAE patients. We screened the whole SERPING1 coding region from 30 subjects out of 16 unrelated families with confirmed diagnosis of HAE due to C1-INH deficiency. Clinical diagnosis was based on symptoms and quantitative and/or functional analysis of C1-INH. We identified fifteen different mutations among which eight were not previously described according to databases. We found five small deletions (c.97_115del19; c.553delG; c.776_782del7; c.1075_1089del15 and c.1353_1354delGA), producing frameshifts leading to premature stop codons; seven missense mutations (c.498C>A; c.550G>C; c.752T>C; c.889G>A; c.1376C>A; c.1396C>T; c.1431C>A); one nonsense mutation (c.1480C>T), and two intronic alterations (c.51+1G>T; c.51+2T>C). Despite the small number of participants in this study, our results show mutations not previously identified in SERPING1 gene. This study represents the first Brazilian HAE cohort evaluated for mutations and it introduces the possibility to perform genetic analysis in case of need for differential diagnosis.

scholarly journals The Genetics of Hereditary Angioedema: A Review

2021 ◽  
Vol 10 (9) ◽  
pp. 2023
Author(s):  
Rosa Santacroce ◽  
Giovanna D'Andrea ◽  
Angela Bruna Maffione ◽  
Maurizio Margaglione ◽  
Maria d'Apolito
Keyword(s):  
Hereditary Angioedema ◽  
Factor Xii ◽  
Inherited Disease ◽  
C1 Inhibitor Deficiency ◽  
C1 Esterase Inhibitor ◽  
New Type ◽  
Diagnostic Applications ◽  
Serping1 Gene ◽  
Esterase Inhibitor

Hereditary angioedema is a rare inherited disorder characterized by recurrent episodes of the accumulation of fluids outside of the blood vessels, causing rapid swelling of tissues in the hands, feet, limbs, face, intestinal tract, or airway. Mutations in SERPING1, the gene that encodes C1-INH (C1 esterase inhibitor), are responsible for the majority of cases of hereditary angioedema. C1 esterase inhibitor (C1-INH) is a major regulator of critical enzymes that are implicated in the cascades of bradykinin generation, which increases the vascular permeability and allows the flow of fluids into the extracellular space and results in angioedema. Moreover, a dominantly inherited disease has been described that has a similar clinical picture to C1-INH-HAE (Hereditary angioedema due to C1 inhibitor deficiency), but with normal C1-INH level and activity. This new type of HAE has no mutation in the SERPING1 gene and it is classified as nC1-INH-HAE (HAE with normal C1-INH). Currently mutations in six different genes have been identified as causing nC1-INH-HAE: factor XII (F12), plasminogen (PLG), angiopoietin 1 (ANGPT1), Kininogen 1 (KNG1), Myoferlin (MYOF), and heparan sulfate (HS)-glucosamine 3-O-sulfotransferase 6 (HS3ST6). In this review we aim to summarize the recent advances in genetic characterization of angioedema and possible future prospects in the identification of new genetic defects in HAE. We also provide an overview of diagnostic applications of genetic biomarkers using NGS technologies (Next Generation Sequencing).

scholarly journals Identification of novel missense mutations in a large number of recent SARS-CoV-2 genome sequences

2020 ◽  
Author(s):  
Hugh Y Cai ◽  
Kimberly K Cai ◽  
Julang Li
Keyword(s):  
Mortality Rate ◽  
Vaccine Development ◽  
Disease Incidence ◽  
Serological Response ◽  
Missense Mutations ◽  
Coding Region ◽  
Public Health Response ◽  
The Impact ◽  
Country Specific ◽  
New Mutations

Abstract Background. SARS-CoV-2 infection has spread to over 200 countries since it was first reported in December of 2019. Significant country-specific variations in infection and mortality rate have been noted. Although country-specific differences in public health response have had a large impact on infection rate control, it is currently unclear as to whether evolution of the virus itself has also contributed to variations in infection and mortality rate. Previous studies on SARS-CoV-2 mutations were based on the analysis of ~ 160 SARS-CoV-2 sequences available until mid-February 2020. 2, 3, 4, 5 By mid-April, > 550 SARS-CoV-2 sequences had been deposited in GenBank, and over 8,200 in the GISAID database. Methods. We performed a sequence analysis on 474 SARS-CoV-2 genomes submitted to GenBank up to April 11, 2020 by multiple alignment using Map to a Reference Assembly and Variants/SNP identification. The results were verified on a larger scale, 8,126 hCoV-19 (SARS-CoV-2) sequences from GISAID database. Results. We identified 5 recently emerged mutations in many isolates (up to 40%). Our analysis highlights 5 frequent new mutations that have emerged since late February 2020. These mutations are: one each missense (non-synonymous) mutation in orf1ab (C1059T), orf3 (G25563T) and orf8 (C27964T), one in 5’UTR (C241T), one in a non-coding region (G29553A). The final mutation (G29553A) was found to be almost exclusive to the US isolates. The first 3 mutations are non-synonymous, leading to amino acid substitutions in the viral protein sequence. Except for C241T, all the novel mutations identified are absent in the isolates from Italy and Spain in the SARS-CoV-2 genomes deposited in GenBank and GISAID. Conclusion. The results of current study indicate that new mutations are emerging as COVID-19 pandemic are spreading to different countries and that geography specific mutants exist. The findings of current study lay the foundation for further investigation into the impact of SARS-CoV-2 mutations on disease incidence, severity, and host immune response. In addition, it may also provide insights into vaccine development and serological response detection for the virus.

scholarly journals Mutational Analysis of a Histone Deacetylase in Drosophila melanogaster: Missense Mutations Suppress Gene Silencing Associated With Position Effect Variegation

Genetics ◽  
2000 ◽  
Vol 154 (2) ◽  
pp. 657-668 ◽  
Author(s):  
Randy Mottus ◽  
Richard E Sobel ◽  
Thomas A Grigliatti
Keyword(s):  
Drosophila Melanogaster ◽  
Histone Deacetylase ◽  
Transcriptional Activity ◽  
Mutational Analysis ◽  
Position Effect ◽  
Transcriptional Regulator ◽  
Position Effect Variegation ◽  
Missense Mutations ◽  
Effect Variegation ◽  
New Mutations

Abstract For many years it has been noted that there is a correlation between acetylation of histones and an increase in transcriptional activity. One prediction, based on this correlation, is that hypomorphic or null mutations in histone deacetylase genes should lead to increased levels of histone acetylation and result in increased levels of transcription. It was therefore surprising when it was reported, in both yeast and fruit flies, that mutations that reduced or eliminated a histone deacetylase resulted in transcriptional silencing of genes subject to telomeric and heterochromatic position effect variegation (PEV). Here we report the first mutational analysis of a histone deacetylase in a multicellular eukaryote by examining six new mutations in HDAC1 of Drosophila melanogaster. We observed a suite of phenotypes accompanying the mutations consistent with the notion that HDAC1 acts as a global transcriptional regulator. However, in contrast to recent findings, here we report that specific missense mutations in the structural gene of HDAC1 suppress the silencing of genes subject to PEV. We propose that the missense mutations reported here are acting as antimorphic mutations that “poison” the deacetylase complex and propose a model that accounts for the various phenotypes associated with lesions in the deacetylase locus.

scholarly journals Screening for Plasminogen Mutations in Hereditary Angioedema Patients

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 402
Author(s):  
Henriette Farkas ◽  
Anna Dóczy ◽  
Edina Szabó ◽  
Lilian Varga ◽  
Dorottya Csuka
Keyword(s):  
Gene Mutation ◽  
Hereditary Angioedema ◽  
Unknown Origin ◽  
Factor Xii ◽  
Gene Encoding ◽  
New Techniques ◽  
Ex Post ◽  
Appropriate Therapy ◽  
Exon 9 ◽  
Serping1 Gene

Hereditary angioedema (HAE) is a rare disease belonging to the group of bradykinin-mediated angioedemas, characterized by recurring edematous episodes involving the subcutaneous and/or submucosal tissues. Most cases of HAE are caused by mutations in the SERPING1 gene encoding C1-inhibitor (C1-INH-HAE); however, mutation analysis identified seven further types of HAE: HAE with Factor XII mutation (FXII-HAE), with plasminogen gene mutation (PLG-HAE), with angiopoietin-1 gene mutation (ANGPT1-HAE), with kininogen-1 gene mutation (KNG1-HAE), with a myoferlin gene mutation (MYOF-HAE), with a heparan sulfate-glucosamine 3-sulfotransferase 6 (HS3ST6) mutation, and hereditary angioedema of unknown origin (U-HAE). We sequenced DNA samples stored from 124 U-HAE patients in the biorepository for exon 9 of the PLG gene. One of the 124 subjects carried the mutation causing a lysine to glutamic acid amino acid exchange at position 330 (K330E). Later, the same PLG mutation was identified in the patient’s son. The introduction of new techniques into genetic testing has increased the number of genes identified. As shown by this study, a biorepository creates the means for the ex-post analysis of recently identified genes in stored DNA samples of the patients. This makes the diagnosis more accurate with the possibility of subsequent family screening and the introduction of appropriate therapy.

scholarly journals In Planta Mutagenesis Determines the Functional Regions of the Wheat Puroindoline Proteins

Genetics ◽  
2009 ◽  
Vol 183 (3) ◽  
pp. 853-860 ◽  
Author(s):  
Leila Feiz ◽  
Brian S. Beecher ◽  
John M. Martin ◽  
Michael J. Giroux
Keyword(s):  
Functional Analysis ◽  
Allelic Variation ◽  
Screening Method ◽  
Point Mutations ◽  
Missense Mutations ◽  
Grain Hardness ◽  
In Planta ◽  
Rich Region ◽  
Critical Function ◽  
The Impact

In planta analysis of protein function in a crop plant could lead to improvements in understanding protein structure/function relationships as well as selective agronomic or end product quality improvements. The requirements for successful in planta analysis are a high mutation rate, an efficient screening method, and a trait with high heritability. Two ideal targets for functional analysis are the Puroindoline a and Puroindoline b (Pina and Pinb, respectively) genes, which together compose the wheat (Triticum aestivum L.) Ha locus that controls grain texture and many wheat end-use properties. Puroindolines (PINs) together impart soft texture, and mutations in either PIN result in hard seed texture. Studies of the PINs' mode of action are limited by low allelic variation. To create new Pin alleles and identify critical function-determining regions, Pin point mutations were created in planta via EMS treatment of a soft wheat. Grain hardness of 46 unique PIN missense alleles was then measured using segregating F2:F3 populations. The impact of individual missense alleles upon PIN function, as measured by grain hardness, ranged from neutral (74%) to intermediate to function abolishing. The percentage of function-abolishing mutations among mutations occurring in both PINA and PINB was higher for PINB, indicating that PINB is more critical to overall Ha function. This is contrary to expectations in that PINB is not as well conserved as PINA. All function-abolishing mutations resulted from structure-disrupting mutations or from missense mutations occurring near the Tryptophan-rich region. This study demonstrates the feasibility of in planta functional analysis of wheat proteins and that the Tryptophan-rich region is the most important region of both PINA and PINB.

Functional analysis of mutations located in the LDL receptor signal sequence coding region

2016 ◽  
Vol 252 ◽  
pp. e43 ◽  
Author(s):  
T. Freiberger ◽  
J. Pavlouskova ◽  
K. Reblova ◽  
L. Tichy ◽  
L. Fajkusova
Keyword(s):  
Functional Analysis ◽  
Signal Sequence ◽  
Ldl Receptor ◽  
Coding Region ◽  
Receptor Signal

scholarly journals Genetic Analysis of Neuroligin 4Y Gene in Autism Population of India

2021 ◽  
Author(s):  
Rajat Hegde ◽  
Smita Hegde ◽  
Suyamindra S. Kulkarni ◽  
Aditya Pandurangi ◽  
Pramod B. Gai ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Genetic Analysis ◽  
Missense Mutation ◽  
Mentally Ill ◽  
Large Population ◽  
Original Structure ◽  
Male Predominance ◽  
Local Configuration ◽  
Autistic Population

Abstract Background Autism is one of the most complex, heterogeneous neurological disorders. It is characterized mainly by abnormal communication, impaired social interaction, and restricted behaviors. Prevalence of autism is not clear in Indian population. Aim The present study hypothesizes that Y chromosome plays role in sex bias of autism in Indian autistic population. To investigate our hypothesis, we underwent genetic analysis of neuroligin 4Y [NLGN4Y] gene by sequencing 85 male autistic children after screening large population of 1,870 mentally ill children from North Karnataka region of India. Result Detailed sequencing of the single targeted gene revealed nine variants including, one novel missense mutation and eight synonymous variants; this accounts for 88.9% of synonymous variants. A single novel missense mutation is predicted to be nonpathogenic on the functions of neuroligin4Y protein but it slightly affects the local configuration by altering the original structure of a protein by changing charge and size of amino acid. Conclusion Probably NLGN4Y gene may not be the risk factor for autism in male children in Indian autistic population. Functional analysis was an important limitation of our study. Therefore, detailed functional analysis is necessary to determine the exact role of novel missense mutation of neuroligin 4Y [NLGN4Y] gene especially in the male predominance of autism in Indian autistic population.

scholarly journals A CIS-DOMINANT MUTATION IN ASPERGILLUS NIDULANS AFFECTING THE EXPRESSION OF THE amdS GENE IN THE PRESENCE OF MUTATIONS IN THE UNLINKED GENE, amdA

Genetics ◽  
1982 ◽  
Vol 102 (2) ◽  
pp. 139-147
Author(s):  
Michael J Hynes
Keyword(s):  
Fine Structure ◽  
Genetic Analysis ◽  
Genetic Mapping ◽  
Gene Function ◽  
The Other ◽  
Structure Mapping ◽  
Dominant Mutation ◽  
Amds Gene ◽  
Very High ◽  
New Mutations

ABSTRACT A mutant producing very high levels of the acetamidase enzyme encoded by the amdS gene has been isolated in a strain containing the amdA7 mutation, which itself causes high levels of this enzyme. Genetic analysis has shown that this mutation, designated amdI66, is adjacent to the amdS gene and is cis-dominant in its effect. The amdI66 mutation has little effect on amdS expression when present in strains not containing the amdA7 mutation. Two other amdA mutations investigated also interact with the amdI66 mutation to result in high acetamidase levels. No interaction between amdI66 and any of the other putative regulatory genes affecting amdS expression has been observed. The amdI66 mutation has been located by fine structure mapping at the extreme end of the controlling region, which has previously been defined by genetic mapping (Hynes 1979). Analysis of this region has been extended by mapping new mutations resulting in loss of amdS expression. One of these defines the most extreme site capable of mutation to loss of gene function found so far.

GENETIC ANALYSIS OF NPC1L1 AND ABCG5/ABCG8 GENES IN AUTOSOMAL DOMINANT HYPERCHOLESTEROLEMIA NOT RELATED TO LDLR OR APOB GENES

2008 ◽  
Vol 9 (1) ◽  
pp. 108
Author(s):  
A. Garcia-Otin ◽  
M. Solanas ◽  
I. deCastro ◽  
B. Martin ◽  
M. Pocovi ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Autosomal Dominant
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