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alpha-Thalassemia caused by two novel splice mutations of the alpha2-globin gene: IVS-I-1 (G>A and G>T).

https://arctichealth.org/en/permalink/ahliterature146989
Source
Hemoglobin. 2009;33(6):519-22
Publication Type
Article
Date
2009
Author
John S Waye
Barry Eng
Fabrizio Dutly
Hannes Frischknecht
Author Affiliation
Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences, Hamilton, Ontario, Canada. waye@hhsc.ca
Source
Hemoglobin. 2009;33(6):519-22
Date
2009
Language
English
Publication Type
Article
Keywords
Aged
Canada
Female
Humans
Introns
Male
Middle Aged
Point Mutation
RNA Splicing - genetics
Sicily
alpha-Globins - genetics
alpha-Thalassemia - genetics
Abstract
We report the identification of two different mutations involving the first nucleotide of intron 1 of the alpha2-globin gene: IVS-I-1 G-->A and G-->T. The available data indicated that both mutations reduce the efficiency of proper mRNA splicing, resulting in alpha(+)-thalassemia (alpha(+)-thal).
PubMed ID
19958200 View in PubMed
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An intron 1 polymorphism in the cholecystokinin-A receptor gene associated with schizophrenia in males.

https://arctichealth.org/en/permalink/ahliterature148550
Source
Acta Psychiatr Scand. 2009 Oct;120(4):281-7
Publication Type
Article
Date
Oct-2009
Author
P. Koefoed
T V O Hansen
D P D Woldbye
T. Werge
O. Mors
T. Hansen
K D Jakobsen
M. Nordentoft
A. Wang
T G Bolwig
J F Rehfeld
Author Affiliation
Department of Neuroscience and Pharmacology, Laboratory for Neuropsychiatry, University of Copenhagen & Centre of Psychiatry, Rigshospitalet, Denmark. pkoefoed@sund.ku.dk
Source
Acta Psychiatr Scand. 2009 Oct;120(4):281-7
Date
Oct-2009
Language
English
Publication Type
Article
Keywords
Adult
Case-Control Studies
Chromosomes, Human, Pair 4 - genetics
Denmark - epidemiology
Diagnostic and Statistical Manual of Mental Disorders
Female
Gene Expression - genetics
Humans
International Classification of Diseases
Introns - genetics
Male
Polymorphism, Single Nucleotide - genetics
RNA Splice Sites - genetics
RNA, Messenger - genetics
Receptor, Cholecystokinin A - genetics
Schizophrenia - diagnosis - epidemiology - genetics
Severity of Illness Index
Sex Distribution
Abstract
To identify whether a genetic variation (rs1800857; IVS1-5T>C) in the neuropeptide cholecystokinin-A receptor (CCKAR) gene is a risk factor in the pathogenesis of schizophrenia.
The variation was analysed in a case-control design comprising 508 patients with schizophrenia and 1619 control subjects. A possible functional impact of this variant on CCKAR protein synthesis through alterations in splicing was analysed in an exon-trapping assay.
In males only, the risk variant, IVS1-5C, was associated with a significantly increased risk of schizophrenia. Carrying one risk allele was associated with an increased risk of 1.74 (Odds Ratio, OR) and homozygosity (CC) was associated with an OR of 3.19. The variation had no impact on protein synthesis of CCKAR.
This is the first report associating the CCKAR gene variant with schizophrenia specifically in men. Our study strengthens the conclusion that a CCKAR dysfunction could be involved in the aetiology of schizophrenia.
PubMed ID
19753663 View in PubMed
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Association between combined properdin and mannose-binding lectin deficiency and infection with Neisseria meningitidis.

https://arctichealth.org/en/permalink/ahliterature29317
Source
Mol Immunol. 2006 Feb;43(5):473-9
Publication Type
Article
Date
Feb-2006
Author
Lise Bathum
Heidi Hansen
Børge Teisner
Claus Koch
Peter Garred
Kirsten Rasmussen
Palle Wang
Author Affiliation
Department of Clinical Biochemistry, Odense University Hospital, Odense, Denmark. l.bathum@ouh.fyns-amt.dk
Source
Mol Immunol. 2006 Feb;43(5):473-9
Date
Feb-2006
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Alleles
Child
Child, Preschool
Chromatography, High Pressure Liquid
Complement Pathway, Alternative
DNA Mutational Analysis
Denmark
Enzyme-Linked Immunosorbent Assay
Epistasis, Genetic
Exons - genetics
Female
Genetic Predisposition to Disease
Humans
Male
Mannose-Binding Lectin - blood - deficiency - genetics
Meningitis, Meningococcal - genetics
Neisseria meningitidis
Pedigree
Polymorphism, Genetic
Promoter Regions (Genetics) - genetics
Properdin - deficiency - genetics
RNA Splice Sites - genetics
Research Support, Non-U.S. Gov't
Risk
Abstract
BACKGROUND: Individuals genetically deficient of properdin are more susceptible to meningococcal disease. Likewise low concentration or decreased biological activity of mannose-binding lectin (MBL) is associated with higher incidence of bacterial infections during childhood. In this study we report our findings in a Danish family with a remarkably high incidence of meningococcal meningitis-in total four cases, one of them fatal. METHODS: Properdin and MBL were quantified by ELISA and the properdin gene was screened for sequence variations using denaturing high-performance liquid chromatography (DHPLC) and subsequent sequencing of abnormal patterns. The MBL gene was genotyped for the three known variant alleles (B, C and D) as well as three promoter polymorphisms (-221Y/X, -550H/L and +4P/Q). RESULTS: Two out of six males with undetectable properdin activity had meningitis. They had also low MBL serum levels or carried an MBL variant allele, whereas high MBL concentrations were measured in three out of four properdin deficient males--without meningitis. A splice site mutation in exon 10 (c.1487-2A>G) was found in the properdin gene and co segregated with biochemically measured properdin deficiency. CONCLUSION: Our results indicate that a combined deficiency of both properdin and MBL increases the risk of infection with Neisseria meningitidis and stress the importance of epistatic genetic interactions in disease susceptibility.
PubMed ID
16337490 View in PubMed
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[A study of the HIV-1 regulatory genes using the polymerase chain reaction].

https://arctichealth.org/en/permalink/ahliterature265675
Source
Vopr Virusol. 2015;60(3):41-4
Publication Type
Article
Date
2015
Author
K A Ryzhov
M N Nosik
A V Kravtchenko
Source
Vopr Virusol. 2015;60(3):41-4
Date
2015
Language
Russian
Publication Type
Article
Keywords
DNA Primers
Disease Progression
Female
Gene Expression Regulation, Viral
Genes, Regulator
Genes, Viral
Genotype
HIV Infections - pathology - virology
HIV-1 - genetics
Humans
Male
Molecular Typing
Moscow
Polymerase Chain Reaction
RNA Splicing
Russia
Siberia
Abstract
In this work, a total of 200 samples from the HIV-infected individuals were analyzed: 50 samples from the Saha Republic (Yakutia), 50 samples from the Vologda Region (City of Cherepovets), and 100 samples from the Moscow Region (Moscow and Moscow Region). All samples were obtained from the patients who were not undergoing antiretroviral therapy. It was detected that the regulatory genes vif, vpr, vpu, rev, tat, and nef were amplified with moderate sensitivity after one-stage amplification. When those samples were analyzed by the nested PCR the detection ratio was much higher. While studying nef-gene the phenomena of the splicing in cells cores was detected at the advanced stages of the HIV-infection (3 and 4 stages). At the same time, the splicing was not detected at the earlier stages of the HIV-infection. This effect might be the cause of the transition from asymptomatic stage of the infection to the advanced stage. It was also shown for the first time that the variability of the regulatory genes correlated with the virus subtype.
PubMed ID
26281306 View in PubMed
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A BAP1 mutation in a Danish family predisposes to uveal melanoma and other cancers.

https://arctichealth.org/en/permalink/ahliterature107790
Source
PLoS One. 2013;8(8):e72144
Publication Type
Article
Date
2013
Author
Lauren G Aoude
Karin Wadt
Anders Bojesen
Dorthe Crüger
Ake Borg
Jeffrey M Trent
Kevin M Brown
Anne-Marie Gerdes
Göran Jönsson
Nicholas K Hayward
Author Affiliation
Oncogenomics Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia ; University of Queensland, Brisbane, Queensland, Australia.
Source
PLoS One. 2013;8(8):e72144
Date
2013
Language
English
Publication Type
Article
Keywords
Adult
Aged
Amino Acid Sequence
Base Sequence
Case-Control Studies
DNA Mutational Analysis
Denmark
Female
Frameshift Mutation
Genetic Association Studies
Genetic Predisposition to Disease
Humans
Loss of Heterozygosity
Male
Melanoma - enzymology - genetics
Middle Aged
Molecular Sequence Data
Pedigree
Protein Isoforms - genetics
RNA Splice Sites
Tumor Suppressor Proteins - genetics
Ubiquitin Thiolesterase - genetics
Uveal Neoplasms - enzymology - genetics
Young Adult
Abstract
Truncating germline mutations in the tumor suppressor gene BRCA-1 associated protein-1 (BAP1) have been reported in families predisposed to developing a wide range of different cancer types including uveal melanoma and cutaneous melanoma. There has also been an association between amelanotic tumor development and germline BAP1 mutation suggesting a possible phenotypic characteristic of BAP1 mutation carriers. Though there have been many types of cancer associated with germline BAP1 mutation, the full spectrum of disease association is yet to be ascertained. Here we describe a Danish family with predominantly uveal melanoma but also a range of other tumor types including lung, neuroendocrine, stomach, and breast cancer; as well as pigmented skin lesions. Whole-exome sequencing identified a BAP1 splice mutation located at c.581-2A>G, which leads to a premature truncation of BAP1 in an individual with uveal melanoma. This mutation was carried by several other family members with melanoma or various cancers. The finding expands on the growing profile of BAP1 as an important uveal and cutaneous melanoma tumor suppressor gene and implicates its involvement in the development of lung, and stomach cancer.
Notes
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Cites: J Clin Oncol. 2012 Nov 10;30(32):e337-4023032617
Cites: J Transl Med. 2012;10:17922935333
Cites: Ann Oncol. 2013 Aug;24(8):2147-5023585512
PubMed ID
23977234 View in PubMed
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The Canadian "National Program for hemophilia mutation testing" database: a ten-year review.

https://arctichealth.org/en/permalink/ahliterature108244
Source
Am J Hematol. 2013 Dec;88(12):1030-4
Publication Type
Article
Date
Dec-2013
Author
Natalia Rydz
Rydz Natalia
Jayne Leggo
Leggo Jayne
Shawn Tinlin
Tinlin Shawn
Paula James
James Paula
David Lillicrap
Lillicrap David
Author Affiliation
Medicine, University of Calgary, Calgary, Alberta, Canada.
Source
Am J Hematol. 2013 Dec;88(12):1030-4
Date
Dec-2013
Language
English
Publication Type
Article
Keywords
Canada - epidemiology
DNA Mutational Analysis
Databases, Genetic
Exons - genetics
Factor IX - genetics
Factor VIII - genetics
Female
Gene Frequency
Genetic Testing
Hemophilia A - epidemiology - genetics
Hemophilia B - epidemiology - genetics
Heterozygote Detection
Humans
Introns - genetics
Male
Mutation
Phenotype
Prenatal Diagnosis
RNA Splice Sites
Retrospective Studies
Sequence Analysis, DNA
Sequence Inversion
Terminology as Topic
von Willebrand Disease, Type 2 - epidemiology - genetics
Abstract
A reference genotyping laboratory was established in 2000 at Queen's University, Kingston, to provide genetic testing for Hemophilia A (HA) and B (HB) and create a Canadian mutation database. Canadian hemophilia treatment centers and genetics clinics provided DNA and clinical information from November 2000 to March 2011. The factor VIII (F8) gene was analyzed in 1,177 patients (47% of HA population) and 787 female family members and the factor IX (F9) gene in 267 patients (47% of HB population) and 123 female family members, using Southern Blot, PCR, conformation sensitive gel electrophoresis, and/or direct sequencing. The mutation detection rates for HA and HB were 91% and 94%, respectively. 380 different F8 mutations were identified: inversions of intron 22 and intron 1, 229 missense, 45 nonsense, eight deletions, 70 frameshifts, 25 splice site, and one compound mutation with a splice site and intron 1 inversion. Of these mutations, 228 were novel to the Hemophilia A Database (HADB, http://hadb.org.uk/). A total 125 different F9 mutations were identified: 80 missense, 12 frameshift, 12 splice site, nine nonsense and seven promoter mutations, three large deletions, and two compound mutations with both missense and nonsense changes. Of these mutations, 36 were novel to the International Haemophilia B Mutation database (http://www.kcl.ac.uk/ip/petergreen/haemBdatabase.html). The Canadian F8 and F9 mutation database reflects the allelic heterogeneity of HA and HB, and is similar to previously described populations. This report represents the largest and longest duration experience of a national hemophilia genotyping program documented, to date.
Notes
Erratum In: Am J Hematol. 2014 Jun;89(6):669Natalia, Rydz [corrected to Rydz, Natalia]; Jayne, Leggo [corrected to Leggo, Jayne]; Shawn, Tinlin [corrected to Tinlin, Shawn]; Paula, James [corrected to James, Paula]; David, Lillicrap [corrected to Lillicrap, David]
PubMed ID
23913812 View in PubMed
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Characterization of BRCA1 and BRCA2 variants found in a Norwegian breast or ovarian cancer cohort.

https://arctichealth.org/en/permalink/ahliterature286172
Source
Fam Cancer. 2017 Jan;16(1):1-16
Publication Type
Article
Date
Jan-2017
Author
Elisabeth Jarhelle
Hilde Monica Frostad Riise Stensland
Lovise Mæhle
Marijke Van Ghelue
Source
Fam Cancer. 2017 Jan;16(1):1-16
Date
Jan-2017
Language
English
Publication Type
Article
Keywords
BRCA1 Protein - genetics - metabolism
BRCA2 Protein - genetics - metabolism
Breast Neoplasms - genetics
Exons
Female
Genetic Predisposition to Disease
Humans
Mutation
Norway
Ovarian Neoplasms - genetics
RNA Splicing
Abstract
Germline mutations in BRCA1 and BRCA2 cause hereditary breast and ovarian cancer. Molecular screening of these two genes in patients with a family history of breast or ovarian cancer has revealed pathogenic variants as well as genetic variants of unknown significance (VUS). These VUS may cause a challenge in the genetic counseling process regarding clinical management of the patient and the family. We investigated 32 variants previously detected in 33 samples from patients with a family history of breast or ovarian cancer. cDNA was analyzed for alternative transcripts and selected missense variants located in the BRCT domains of BRCA1 were assessed for their trans-activation ability. Although an extensive cDNA analysis was done, only three of the 32 variants appeared to affect the splice-process (BRCA1 c.213-5T>A, BRCA1 c.5434C>G and BRCA2 c.68-7T>A). In addition, two variants located in the BRCT domains of BRCA1 (c.5075A>C p.Asp1692Ala and c.5513T>G p.Val1838Gly) were shown to abolish the BRCT domain trans-activation ability, whereas BRCA1 c.5125G>A p.Gly1709Arg exhibited equal trans-activation capability as the WT domain. These functional studies may offer further insights into the pathogenicity of certain identified variants; however, this assay is only applicable for a subset of missense variants.
PubMed ID
27495310 View in PubMed
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Characterization of mutations in patients with autoimmune polyglandular syndrome type 1 (APS1).

https://arctichealth.org/en/permalink/ahliterature203313
Source
Hum Genet. 1998 Dec;103(6):681-5
Publication Type
Article
Date
Dec-1998
Author
C Y Wang
A. Davoodi-Semiromi
W. Huang
E. Connor
J D Shi
J X She
Author Affiliation
Department of Pathology, Immunology and Laboratory Medicine, Center for Mammalian Genetics, College of Medicine, University of Florida, Gainesville 32610, USA.
Source
Hum Genet. 1998 Dec;103(6):681-5
Date
Dec-1998
Language
English
Publication Type
Article
Keywords
European Continental Ancestry Group
Female
Finland
Frameshift Mutation
Genetic Counseling
Haplotypes
Humans
Male
Mutagenesis, Insertional
Mutation
Polyendocrinopathies, Autoimmune - diagnosis - genetics
Polymerase Chain Reaction
Polymorphism, Genetic
RNA Splicing
Sequence Analysis, DNA
Sequence Deletion
Syndrome
Transcription Factors - genetics
United States
Abstract
Autoimmune polyglandular syndrome type 1 (APS1), also known as autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), is an autosomal recessive disorder characterized by the failure of several endocrine glands as well as nonendocrine organs. The autoimmune regulator (AIRE) gene responsible for APS1 on chromosome 21q22.3 has recently been identified. Here, we have characterized mutations in the AIRE gene by direct DNA sequencing in 16 unrelated APS1 families ascertained mainly from the USA. Our analyses identified four different mutations (a 13-bp deletion, a 2-bp insertion, one nonsense mutation, and one potential splice/donor site mutation) that are likely to be pathogenic. Fifty-six percent (9/16) of the patients contained at least one copy of a 13-bp deletion (1094-1106del) in exon 8 (seven homozygotes and two compound heterozygotes). A nonsense mutation (R257X) in exon 6 was also found in 31.3% (5/16) of the USA patients. These data are important for genetic diagnosis and counseling for families with autoimmune endocrine syndromes.
PubMed ID
9921903 View in PubMed
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Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark.

https://arctichealth.org/en/permalink/ahliterature284663
Source
Eur J Hum Genet. 2016 Jul;24(7):1071-9
Publication Type
Article
Date
Jul-2016
Author
Galuh D N Astuti
Mette Bertelsen
Markus N Preising
Muhammad Ajmal
Birgit Lorenz
Sultana M H Faradz
Raheel Qamar
Rob W J Collin
Thomas Rosenberg
Frans P M Cremers
Source
Eur J Hum Genet. 2016 Jul;24(7):1071-9
Date
Jul-2016
Language
English
Publication Type
Article
Keywords
Adult
Child
Denmark
Female
Heterozygote
Humans
Infant
Leber Congenital Amaurosis - genetics - pathology
Male
Mutation Rate
Mutation, Missense
Pedigree
RNA Splicing
cis-trans-Isomerases - genetics
Abstract
Leber congenital amaurosis (LCA) represents the most severe form of inherited retinal dystrophies with an onset during the first year of life. Currently, 21 genes are known to be associated with LCA and recurrent mutations have been observed in AIPL1, CEP290, CRB1 and GUCY2D. In addition, sequence analysis of LRAT and RPE65 may be important in view of treatments that are emerging for patients carrying variants in these genes. Screening of the aforementioned variants and genes was performed in 64 Danish LCA probands. Upon the identification of heterozygous variants, Sanger sequencing was performed of the relevant genes to identify the second allele. In combination with prior arrayed primer extension analysis, this led to the identification of two variants in 42 of 86 cases (49%). Remarkably, biallelic RPE65 variants were identified in 16% of the cases, and one novel variant, p.(D110G), was found in seven RPE65 alleles. We also collected all previously published RPE65 variants, identified in 914 alleles of 539 patients with LCA or early-onset retinitis pigmentosa, and deposited them in the RPE65 Leiden Open Variation Database (LOVD). The in silico pathogenicity assessment of the missense and noncanonical splice site variants, as well as an analysis of their frequency in ~60?000 control individuals, rendered 864 of the alleles to affect function or probably affect function. This comprehensive database can now be used to select patients eligible for gene augmentation or retinoid supplementation therapies.
Notes
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PubMed ID
26626312 View in PubMed
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Disruption of an exon splicing enhancer in exon 3 of MLH1 is the cause of HNPCC in a Quebec family.

https://arctichealth.org/en/permalink/ahliterature174535
Source
J Med Genet. 2006 Feb;43(2):153-6
Publication Type
Article
Date
Feb-2006
Author
S. McVety
L. Li
P H Gordon
G. Chong
W D Foulkes
Source
J Med Genet. 2006 Feb;43(2):153-6
Date
Feb-2006
Language
English
Publication Type
Article
Keywords
Adaptor Proteins, Signal Transducing
Animals
COS Cells
Carrier Proteins - genetics
Cercopithecus aethiops
Colorectal Neoplasms, Hereditary Nonpolyposis - genetics
Exons - genetics
Humans
Nuclear Proteins - genetics
Point Mutation - genetics
Quebec
RNA Splice Sites - genetics
RNA Splicing - genetics
Regulatory Sequences, Ribonucleic Acid - genetics
Abstract
A 3 bp deletion located at the 5' end of exon 3 of MLH1, resulting in deletion of exon 3 from RNA, was recently identified.
That this mutation disrupts an exon splicing enhancer (ESE) because it occurs in a purine-rich sequence previously identified as an ESE in other genes, and ESEs are often found in exons with splice signals that deviate from the consensus signals, as does the 3' splice signal in exon 3 of MLH1.
The 3 bp deletion and several other mutations were created by polymerase chain reaction mutagenesis and tested using an in vitro splicing assay. Both mutant and wild type exon 3 sequences were cloned into an exon trapping vector and transiently expressed in Cos-1 cells.
Analysis of the RNA indicates that the 3 bp deletion c.213_215delAGA (gi:28559089, NM_000249.2), a silent mutation c.216T-->C, a missense mutation c.214G-->C, and a nonsense mutation c.214G-->T all cause varying degrees of exon skipping, suggesting the presence of an ESE at the 5' end of exon 3. These mutations are situated in a GAAGAT sequence 3 bp downstream from the start of exon 3.
The results of the splicing assay suggest that inclusion of exon 3 in the mRNA is ESE dependent. The exon 3 ESE is not recognised by all available motif scoring matrices, highlighting the importance of RNA analysis in the detection of ESE disrupting mutations.
Notes
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PubMed ID
15923275 View in PubMed
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53 records – page 1 of 6.