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Golovleva, Irina
Publications (10 of 64) Show all publications
Jonsson, F., Boström, I. M., Österman, L., Sandgren, O., Burstedt, M., Holmberg, M. & Golovleva, I. (2018). ATP-binding cassette subfamily A, member 4 intronic variants c.4773+3A > G and c.5461-10T > C cause Stargardt disease due to defective splicing. Acta Ophthalmologica, 96(7), 737-743
Open this publication in new window or tab >>ATP-binding cassette subfamily A, member 4 intronic variants c.4773+3A > G and c.5461-10T > C cause Stargardt disease due to defective splicing
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2018 (English)In: Acta Ophthalmologica, ISSN 1755-375X, E-ISSN 1755-3768, Vol. 96, no 7, p. 737-743Article in journal (Refereed) Published
Abstract [en]

Purpose

Inherited retinal dystrophies (IRDs) represent a group of progressive conditions affecting the retina. There is a great genetic heterogeneity causing IRDs, and to date, more than 260 genes are associated with IRDs. Stargardt disease, type 1 (STGD1) or macular degeneration with flecks, STGD1 represents a disease with early onset, central visual impairment, frequent appearance of yellowish flecks and mutations in the ATP‐binding cassette subfamily A, member 4 (ABCA4) gene. A large number of intronic sequence variants in ABCA4 have been considered pathogenic although their functional effect was seldom demonstrated. In this study, we aimed to reveal how intronic variants present in patients with Stargardt from the same Swedish family affect splicing.

Methods

The splicing of the ABCA4 gene was studied in human embryonic kidney cells, HEK293T, and in human retinal pigment epithelium cells, ARPE‐19, using a minigene system containing variants c.4773+3A>G and c.5461‐10T>C.

Results

We showed that both ABCA4 variants, c.4773+3A>G and c.5461‐10T>C, cause aberrant splicing of the ABCA4 minigene resulting in exon skipping. We also demonstrated that splicing of ABCA4 has different outcomes depending on transfected cell type.

Conclusion

Two intronic variants c.4773+3A>G and c.5461‐10T>C, both predicted to affect splicing, are indeed disease‐causing mutations due to skipping of exons 33, 34, 39 and 40 of ABCA4 gene. The experimental proof that ABCA4 mutations in STGD patients affect protein function is crucial for their inclusion to future clinical trials; therefore, functional testing of all ABCA4 intronic variants associated with Stargardt disease by minigene technology is desirable.

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
Keywords
ABCA4, intronic variants, mutation, splicing, Stargardt disease
National Category
Genetics
Identifiers
urn:nbn:se:umu:diva-154068 (URN)10.1111/aos.13676 (DOI)000451035500011 ()29461686 (PubMedID)
Funder
Västerbotten County Council
Available from: 2018-12-12 Created: 2018-12-12 Last updated: 2018-12-12Bibliographically approved
Weisschuh, N., Stingl, K., Audo, I., Biskup, S., Bocquet, B., Branham, K., . . . Kohl, S. (2018). Mutations in the gene PDE6C encoding the catalytic subunit of the cone photoreceptor phosphodiesterase in patients with achromatopsia. Human Mutation, 39(10), 1366-1371
Open this publication in new window or tab >>Mutations in the gene PDE6C encoding the catalytic subunit of the cone photoreceptor phosphodiesterase in patients with achromatopsia
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2018 (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 39, no 10, p. 1366-1371Article in journal (Refereed) Published
Abstract [en]

Biallelic PDE6C mutations are a known cause for rod monochromacy, better known as autosomal recessive achromatopsia (ACHM), and early-onset cone photoreceptor dysfunction. PDE6C encodes the catalytic alpha'-subunit of the cone photoreceptor phosphodiesterase, thereby constituting an essential part of the phototransduction cascade. Here, we present the results of a study comprising 176 genetically preselected patients who remained unsolved after Sanger sequencing of the most frequent genes accounting for ACHM, and were subsequently screened for exonic and splice site variants in PDE6C applying a targeted next generation sequencing approach. We were able to identify potentially pathogenic biallelic variants in 15 index cases. The mutation spectrum comprises 18 different alleles, 15 of which are novel. Our study significantly contributes to the mutation spectrum of PDE6C and allows for a realistic estimate of the prevalence of PDE6C mutations in ACHM since our entire ACHM cohort comprises 1,074 independent families.

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
Keywords
achromatopsia, cone phosphodiesterase, mutation spectrum and prevalence, PDE6C
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-152387 (URN)10.1002/humu.23606 (DOI)000444948000008 ()30080950 (PubMedID)
Available from: 2018-10-05 Created: 2018-10-05 Last updated: 2018-10-05Bibliographically approved
Jonsson, F., Burstedt, M., Kellgren, T. & Golovleva, I. (2018). Non-homologous recombination between Alu and LINE-1 repeats results in a 91 kb deletion in MERTK causing severe retinitis pigmentosa. Molecular Vision, 24, 667-678
Open this publication in new window or tab >>Non-homologous recombination between Alu and LINE-1 repeats results in a 91 kb deletion in MERTK causing severe retinitis pigmentosa
2018 (English)In: Molecular Vision, ISSN 1090-0535, E-ISSN 1090-0535, Vol. 24, p. 667-678Article in journal (Refereed) Published
Abstract [en]

Purpose: Retinitis pigmentosa (RP) represents a large group of inherited retinal diseases characterized by clinical and genetic heterogeneity. Among patients with RP in northern Sweden, we identified two severely affected siblings and aimed to reveal a genetic cause underlying their disease.

Methods: Whole exome sequencing (WES) was performed on both affected individuals. Sequence variants were filtered using a custom pipeline to find a rare or novel variant predicted to affect protein function. Genome-wide genotyping was used to identify copy number variants (CNVs) and homozygous regions with potential disease causative genes.

Results: WES uncovered a novel heterozygous variant in the MER proto-oncogene, tyrosine kinase (MERTK) gene, c.2309A>G, p.Glu770Gly located in the tyrosine kinase domain and predicted to be likely pathogenic. The second variant, a large heterozygous deletion encompassing exons 1 to 7 of the MERTK gene, was revealed with genome-wide genotyping. The CNV analysis suggested breakpoints of the deletion, in the 5′-untranslated region and in intron 7. We identified genomic sequences at the site of the deletion as part of L1ME4b (LINE/L1) and AluSx3 that indicated a non-homologous recombination as a mechanism of the deletion evolvement.

Conclusions: Patients with RP in this study were carriers of two novel allelic mutations in the MERTK gene, a missense variant in exon 17 and an approximate 91 kb genomic deletion. Mapping of the deletion breakpoints allowed molecular testing of a cohort of patients with RP with allele-specific PCR. These findings provide additional information about mutations in MERTK for molecular testing of unsolved recessive RP cases and highlight the necessity for analysis of large genomic deletions.

National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-153121 (URN)000447627900001 ()2-s2.0-85055736745 (Scopus ID)
Available from: 2018-11-12 Created: 2018-11-12 Last updated: 2018-11-12Bibliographically approved
Burstedt, M., Jonsson, F., Boström, I. M. & Golovleva, I. (2018). Phenotypic expression of EYS mutations in patients with autosomal recessive retinitis pigmentosa in northern Sweden. Paper presented at Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), APR 29-MAY 03, 2018, Honolulu, HI. Investigative Ophthalmology and Visual Science, 59(9)
Open this publication in new window or tab >>Phenotypic expression of EYS mutations in patients with autosomal recessive retinitis pigmentosa in northern Sweden
2018 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 59, no 9Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Purpose : To describe clinical phenotype in patients of northern Sweden affected by recessive retinitis pigmentosa (ARRP) caused by mutations in Eyes Shut Homolog (Drosophila) (EYS) gene.

Methods : Whole exome sequencing (WES) and multiple ligation dependent prode amplification (MLPA) were used for identification of EYS sequence variants in a cohort of ARRP patients (n=148) from northern Sweden. The patients with EYS mutations were ophthalmologically examined over time using visual acuity (ETDRS), visual fields, slit lamp and fundus examination and ocular coherence tomography (OCT). Dark adaptometry and full-field electroretionograms (ERG) was performed.

Results : Phenotype characterization was done in 13 ARRP cases with EYS mutations representing five bi-allelic sequence variants, three of which were novel. Only one variant was detected in two cases. The phenotypic outcome was predominately presented as classical RP aggravating in young adulthood. However, among these patients we observed a variation of phenotypic expression with initial paracentral to central macular affection of the retina and areolar retinal degeneration with electrophysiological outcome of only slightly subnormal responses of both rods and cones in late adulthood (60 y/o), clinically defined as areolar atrophy.

Conclusions : The EYS mutations account for 10% of ARRP in northern Sweden. The phenotype presents both typical classical RP and chorioretinal degenerative retinal disease, areolar dystrophy. This suggests that molecular genetic testing of the EYS is crucial when both RP and pattern macular diseases are clinically diagnosed.

Place, publisher, year, edition, pages
The Association for Research in Vision and Ophthalmology, Inc., 2018
National Category
Ophthalmology
Identifiers
urn:nbn:se:umu:diva-152275 (URN)000442912500004 ()
Conference
Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), APR 29-MAY 03, 2018, Honolulu, HI
Available from: 2018-10-02 Created: 2018-10-02 Last updated: 2018-10-02Bibliographically approved
Djusberg, E., Jernberg, E., Thysell, E., Golovleva, I., Lundberg, P., Crnalic, S., . . . Wikström, P. (2017). High Levels of the AR-V7 Splice Variant and Co-Amplification of the Golgi Protein Coding YIPF6 in AR Amplified Prostate Cancer Bone Metastases. The Prostate, 77(6), 625-638
Open this publication in new window or tab >>High Levels of the AR-V7 Splice Variant and Co-Amplification of the Golgi Protein Coding YIPF6 in AR Amplified Prostate Cancer Bone Metastases
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2017 (English)In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 77, no 6, p. 625-638Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The relation between androgen receptor (AR) gene amplification and other mechanisms behind castration-resistant prostate cancer (CRPC), such as expression of constitutively active AR variants and steroid-converting enzymes has been poorly examined. Specific aim was to examine AR amplification in PC bone metastases and to explore molecular and functional consequences of this, with the long-term goal of identifying novel molecular targets for treatment. METHODS: Gene amplification was assessed by fluorescence in situ hybridization in cryo-sections of clinical PC bone metastases (n = 40) and by PCR-based copy number variation analysis. Whole genome mRNA expression was analyzed using H12 Illumina Beadchip arrays and specific transcript levels were quantified by qRT-PCR. Protein localization was analyzed using immunohistochemistry and confocal microscopy. The YIPF6 mRNA expression was transiently knocked down and stably overexpressed in the 22Rv1 cell line as representative for CRPC, and effects on cell proliferation, colony formation, migration, and invasion were determined in vitro. Extracellular vesicles (EVs) were isolated from cell cultures using size-exclusion chromatography and enumerated by nanoparticle tracking analysis. Protein content was identified by LC-MS/MS analysis. Blood coagulation was measured as activated partial thromboplastin time (APTT). Functional enrichment analysis was performed using the MetaCore software. RESULTS: AR amplification was detected in 16 (53%) of the bone metastases examined from CRPC patients (n = 30), and in none from the untreated patients (n = 10). Metastases with AR amplification showed high AR and AR-V7 mRNA levels, increased nuclear AR immunostaining, and co-amplification of genes such as YIPF6 in the AR proximity at Xq12. The YIPF6 protein was localized to the Golgi apparatus. YIPF6 overexpression in 22Rv1 cells resulted in reduced cell proliferation and colony formation, and in enhanced EV secretion. EVs from YIPF6 overproducing 22Rv1 cells were enriched for proteins involved in blood coagulation and, accordingly, decreased the APTT in a dose-dependent fashion. CONCLUSIONS: AR amplified CRPC bone metastases show high AR-V7 expression that probably gives resistance to AR-targeting drugs. Co-amplification of the Golgi protein coding YIPF6 gene with the AR may enhance the secretion of pro-coagulative EVs from cancer cells and thereby stimulate tumor progression and increase the coagulopathy risk in CRPC patients.

Place, publisher, year, edition, pages
Wiley-Blackwell Publishing Inc., 2017
Keywords
androgen receptor variant 7, AKR1C3, extracellular vesicles, exosomes, blood coagulation
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-131817 (URN)10.1002/pros.23307 (DOI)000397496300007 ()28144969 (PubMedID)
Available from: 2017-02-22 Created: 2017-02-22 Last updated: 2018-06-09Bibliographically approved
Johansson, G., Brannstrom, T., Andersson, U., Golovleva, I. & Melin, B. (2017). MOLECULAR CLASSIFICATION OF MALIGNANT GLIOMA. Paper presented at 5th Quadrennial Meeting of the World-Federation-of-Neuro-Oncology-Societies (WFNOS), MAY 04-07, 2017, Zurich, SWITZERLAND. Neuro-Oncology, 19(Supplement: 3), 88-88, Article ID Meeting Abstract: P10.15.
Open this publication in new window or tab >>MOLECULAR CLASSIFICATION OF MALIGNANT GLIOMA
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2017 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 19, no Supplement: 3, p. 88-88, article id Meeting Abstract: P10.15Article in journal, Meeting abstract (Refereed) Published
Place, publisher, year, edition, pages
OXFORD UNIV PRESS INC, 2017
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-136983 (URN)000402732900335 ()
Conference
5th Quadrennial Meeting of the World-Federation-of-Neuro-Oncology-Societies (WFNOS), MAY 04-07, 2017, Zurich, SWITZERLAND
Available from: 2017-06-30 Created: 2017-06-30 Last updated: 2019-05-10Bibliographically approved
Vikberg, A.-L., Vooder, T., Lokk, K., Annilo, T. & Golovleva, I. (2017). Mutation analysis and copy number alterations of KIF23 in non-small-cell lung cancer exhibiting KIF23 over-expression. OncoTargets and Therapy, 10, 4969-4979
Open this publication in new window or tab >>Mutation analysis and copy number alterations of KIF23 in non-small-cell lung cancer exhibiting KIF23 over-expression
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2017 (English)In: OncoTargets and Therapy, ISSN 1178-6930, Vol. 10, p. 4969-4979Article in journal (Refereed) Published
Abstract [en]

KIF23 was recently suggested to be a potential molecular target for the treatment of lung cancer. This proposal is based on elevated expression of KIF23 in several tumors affecting breast, lung, brain, and liver, and also on the presence of KIF23 mutations in melanoma and colorectal cancer. Recently, we identified a mutation in the KIF23 gene causing a rare hereditary form of dyserythropoietic anemia (CDA III) with predisposition to blood cancer. We suggested that KIF23 overexpression in tumors might be due to the presence of activating somatic mutations, and therefore, mutation screening of the KIF23 in 15 non-small-cell lung cancer (NSCLC) cases with elevated expression level of KIF23 was undertaken. Eight sequence variants were found in all samples. Furthermore, one variant was present in two cases, and one variant was case specific. Nine variants were previously reported while one variant lacks frequency information. Nine of ten cases available for single nucleotide polymorphism-array analysis demonstrated aberrant karyotypes with additional copy of entire chromosome 15. Thus, no activating somatic mutations in coding regions of the KIF23 were found. Furthermore, no mutations were detected in cell cycle genes homology region in KIF23 promoter responsible for p53-dependent repression of KIF23 expression. We showed that the elevated level of KIF23 could be due to additional copy of chromosome 15 demonstrated in 90% of NSCLC cases analyzed in this study. Considering the crucial role of KIF23 in the final step of mitosis, the gene is a potential molecular marker, and for better understanding of its role in cancer development, more tumors should be analyzed.

Place, publisher, year, edition, pages
DOVE MEDICAL PRESS LTD, 2017
Keywords
KIF23, overexpression, mutation, copy number alteration, CNA, lung cancer
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-141225 (URN)10.2147/OTT.S138420 (DOI)000412742500004 ()
Available from: 2017-11-06 Created: 2017-11-06 Last updated: 2018-06-09Bibliographically approved
Liljeholm, M., Vikberg, A.-L., Golovleva, I., Sandström, H. & Wahlin, A. (2016). Congenital Dyserythropoietic Anemia Type III and Primary Hemochromatosis; Coexistence of Mutations in KIF23 and HFE.. Journal of Hematology and Blood Disorders, 1(2), Article ID 203.
Open this publication in new window or tab >>Congenital Dyserythropoietic Anemia Type III and Primary Hemochromatosis; Coexistence of Mutations in KIF23 and HFE.
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2016 (English)In: Journal of Hematology and Blood Disorders, Vol. 1, no 2, article id 203Article in journal (Refereed) Published
Abstract [en]

Background: Congenital dyserythropoietic anemia type III (CDA III) can be caused by mutation in KIF23. CDA III differs from CDA I and II in the sense that secondary hemochromatosis has not been reported. However, we have observed elevated serum ferritin in a CDA III family. Since primary hemochromatosis is common in Northern Europe we decided to screen the family for HFE mutations.

Aim: Study clinical appearance and prevalence of HFE gene mutations, C282Y and H63D, in a CDA III family. 

Methods: DNA from 37 CDA III patients and 21 non-affected siblings was genotyped. Iron status from EDTA plasma was measured in 32 of the CDA III patients and 18 of the non-affected siblings.

Results: Out of 37 CDA III patients, 18 carried heterozygous HFE mutations and six were compound heterozygotes. Out of 21 CDA III negative siblings, nine had heterozygous HFE mutations, two were homozygous (one H63D and one C282Y), and two were compound heterozygous. None of the patients with wt HFE, regardless of CDA III status, suffered from iron overload. Four patients with HFE mutations needed treatment with phlebotomy to normalize ferritin and transferrin iron saturation; one CDA III negative patient with homozygous C282Y, two CDA III patients with heterozygous HFE mutations and one CDA III case with compound heterozygosity.

Conclusion: HFE mutations were found in 65 % of CDA III patients and in 62 % of their CDA III negative siblings. Heterozygous HFE mutation, C282Y and even H63D, can cause iron overload when occurring concomitantly with CDA III.

Place, publisher, year, edition, pages
Annex Publishers, 2016
Keywords
Congenital dyserythropoietic anemia; Hereditary hemochromatosis; Iron overload; HFE gene; KIF23 gene
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-117453 (URN)
Available from: 2016-02-29 Created: 2016-02-29 Last updated: 2018-06-07Bibliographically approved
Ghasimi, S., Wibom, C., Dahlin, A. M., Brännström, T., Golovleva, I., Andersson, U. & Melin, B. (2016). Genetic risk variants in the CDKN2A/B, RTEL1 and EGFR genes are associated with somatic biomarkers in glioma. Journal of Neuro-Oncology, 127(3), 483-492
Open this publication in new window or tab >>Genetic risk variants in the CDKN2A/B, RTEL1 and EGFR genes are associated with somatic biomarkers in glioma
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2016 (English)In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 127, no 3, p. 483-492Article in journal (Refereed) Published
Abstract [en]

During the last years, genome wide association studies have discovered common germline genetic variants associated with specific glioma subtypes. We aimed to study the association between these germline risk variants and tumor phenotypes, including copy number aberrations and protein expression. A total of 91 glioma patients were included. Thirteen well known genetic risk variants in TERT, EGFR, CCDC26, CDKN2A, CDKN2B, PHLDB1, TP53, and RTEL1 were selected for investigation of possible correlations with the glioma somatic markers: EGFR amplification, 1p/19q codeletion and protein expression of p53, Ki-67, and mutated IDH1. The CDKN2A/B risk variant, rs4977756, and the CDKN2B risk variant, rs1412829 were inversely associated (p = 0.049 and p = 0.002, respectively) with absence of a mutated IDH1, i.e., the majority of patients homozygous for the risk allele showed no or low expression of mutated IDH1. The RTEL1 risk variant, rs6010620 was associated (p = 0.013) with not having 1p/19q codeletion, i.e., the majority of patients homozygous for the risk allele did not show 1p/19q codeletion. In addition, the EGFR risk variant rs17172430 and the CDKN2B risk variant rs1412829, both showed a trend for association (p = 0.055 and p = 0.051, respectively) with increased EGFR copy number, i.e., the majority of patients homozygote for the risk alleles showed chromosomal gain or amplification of EGFR. Our findings indicate that CDKN2A/B risk genotypes are associated with primary glioblastoma without IDH mutation, and that there is an inverse association between RTEL1 risk genotypes and 1p/19q codeletion, suggesting that these genetic variants have a molecular impact on the genesis of high graded brain tumors. Further experimental studies are needed to delineate the functional mechanism of the association between genotype and somatic genetic aberrations.

Keywords
CDKN2A/B, EGFR, RTEL1, SNP, FISH, ASCAT
National Category
Cancer and Oncology Neurology
Identifiers
urn:nbn:se:umu:diva-121460 (URN)10.1007/s11060-016-2066-4 (DOI)000374463800009 ()26839018 (PubMedID)
Available from: 2016-06-22 Created: 2016-06-02 Last updated: 2018-06-07Bibliographically approved
Golovleva, I., Jonsson, F. & Burstedt, M. (2016). Heterogeneity and complexity of EYS mutations in autosomal recessive retinitis pigmentosa in northern Sweden. Paper presented at Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), MAY 01-05, 2016, Seattle, WA. Investigative Ophthalmology and Visual Science, 57(12)
Open this publication in new window or tab >>Heterogeneity and complexity of EYS mutations in autosomal recessive retinitis pigmentosa in northern Sweden
2016 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 57, no 12Article in journal, Meeting abstract (Refereed) Published
Place, publisher, year, edition, pages
ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2016
National Category
Ophthalmology
Identifiers
urn:nbn:se:umu:diva-132853 (URN)000394210202022 ()
Conference
Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), MAY 01-05, 2016, Seattle, WA
Note

Meeting Abstract: 3136

Available from: 2017-03-29 Created: 2017-03-29 Last updated: 2018-06-09Bibliographically approved
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