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Sandgren, Ola
Publications (10 of 21) 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
Jonsson, F., Byström, B., Davidson, A. E., Backman, L. J., Kellgren, T., Tuft, S. J., . . . Golovleva, I. (2015). Mutations in Collagen, Type XVII, Alpha 1 (COL17A1) Cause Epithelial Recurrent Erosion Dystrophy (ERED). Human Mutation, 36(4), 463-473
Open this publication in new window or tab >>Mutations in Collagen, Type XVII, Alpha 1 (COL17A1) Cause Epithelial Recurrent Erosion Dystrophy (ERED)
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2015 (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, no 4, p. 463-473Article in journal (Refereed) Published
Abstract [en]

Corneal dystrophies are a clinically and genetically heterogeneous group of inherited disorders that bilaterally affect corneal transparency. They are defined according to the corneal layer affected and by their genetic cause. In this study, we identified a dominantly inherited epithelial recurrent erosion dystrophy (ERED)-like disease that is common in northern Sweden. Whole-exome sequencing resulted in the identification of a novel mutation, c.2816C>T, p.T939I, in the COL17A1 gene, which encodes collagen type XVII alpha 1. The variant segregated with disease in a genealogically expanded pedigree dating back 200 years. We also investigated a unique COL17A1 synonymous variant, c.3156C>T, identified in a previously reported unrelated dominant ERED-like family linked to a locus on chromosome 10q23-q24 encompassing COL17A1. We show that this variant introduces a cryptic donor site resulting in aberrant pre-mRNA splicing and is highly likely to be pathogenic. Bi-allelic COL17A1 mutations have previously been associated with a recessive skin disorder, junctional epidermolysis bullosa, with recurrent corneal erosions being reported in some cases. Our findings implicate presumed gain-of-function COL17A1 mutations causing dominantly inherited ERED and improve understanding of the underlying pathology.

Place, publisher, year, edition, pages
John Wiley & Sons, 2015
Keywords
COL17A1, BP180, cornea dystrophy, ERED, ddPCR
National Category
Medical Bioscience
Identifiers
urn:nbn:se:umu:diva-103155 (URN)10.1002/humu.22764 (DOI)000352304200011 ()25676728 (PubMedID)
Note

Contract grant sponsors: Umeå University and Västerbotten County Council, Research and Development Foundation sponsored by Västerbotten County Council, Cronqvists Stiftelse (administered by The Swedish Society of Medicine); Ögonfonden, Stiftelsen KMA; the National Swedish Research Council (521-2013-2612); National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology; Moorfields Special Trustees; Moorfields Eye Charity; the Lanvern foundation.

Available from: 2015-05-29 Created: 2015-05-18 Last updated: 2018-06-07Bibliographically approved
Jonsson, F., Burstedt, M. S., Sandgren, O., Norberg, A. & Golovleva, I. (2014). Genetic heterogeneity and clinical outcome in a Swedish family with retinal degeneration caused by mutations in CRB1 and ABCA4 genes. In: Retinal Degenerative Diseases: Mechanisms and Experimental Therapy. Paper presented at 15th International Symposium on Retinal Degeneration (RD) Location: GERMANY Date: JUL 16-21, 2012 (pp. 177-183). Springer Berlin/Heidelberg, 801
Open this publication in new window or tab >>Genetic heterogeneity and clinical outcome in a Swedish family with retinal degeneration caused by mutations in CRB1 and ABCA4 genes
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2014 (English)In: Retinal Degenerative Diseases: Mechanisms and Experimental Therapy, Springer Berlin/Heidelberg, 2014, Vol. 801, p. 177-183Conference paper, Published paper (Refereed)
Abstract [en]

Genetic mechanisms underlying severe retinal dystrophy in a large Swedish family presenting two distinct phenotypes, Leber congenital amaurosis and Stargardt disease were investigated. In the family, four patients with Leber congenital amaurosis were homozygous for a novel c.2557C>T (p.Q853X) mutation in the CRB1 gene, while of two cases with Stargardt disease, one was homozygous for c.5461-10T>C in the ABCA4 gene and another was a compound heterozygous for c.5461-10T>C and a novel ABCA4 mutation c.4773+3 A>G. Sequence analysis of the entire ABCA4 gene in patients with Stargardt disease revealed complex alleles with additional sequence variants.Our results provide evidence of genetic complexity causative of different clinical features present in the same family, which is an obvious challenge for ophthalmologists, molecular geneticists and genetic counsellors.

Place, publisher, year, edition, pages
Springer Berlin/Heidelberg, 2014
Series
Advances in Experimental Medicine and Biology, ISSN 0065-2598 ; 801
Keywords
applanation resonance tonometry, ART, glaucoma, intraocular pressure, ISO standard, tonometry
National Category
Ophthalmology Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-101488 (URN)10.1007/978-1-4614-3209-8_23 (DOI)000350418200024 ()24664696 (PubMedID)978-1-4614-3209-8 (ISBN)978-1-4614-3208-1 (ISBN)
Conference
15th International Symposium on Retinal Degeneration (RD) Location: GERMANY Date: JUL 16-21, 2012
Available from: 2015-03-31 Created: 2015-03-31 Last updated: 2018-06-07Bibliographically approved
Jonsson, F., Burstedt, M. S., Sandgren, O., Norberg, A. & Golovleva, I. (2013). Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family. European Journal of Human Genetics, 21(11), 1266-1271
Open this publication in new window or tab >>Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family
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2013 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 21, no 11, p. 1266-1271Article in journal (Refereed) Published
Abstract [en]

This study aimed to identify genetic mechanisms underlying severe retinal degeneration in one large family from northern Sweden, members of which presented with early-onset autosomal recessive retinitis pigmentosa and juvenile macular dystrophy. The clinical records of affected family members were analysed retrospectively and ophthalmological and electrophysiological examinations were performed in selected cases. Mutation screening was initially performed with microarrays, interrogating known mutations in the genes associated with recessive retinitis pigmentosa, Leber congenital amaurosis and Stargardt disease. Searching for homozygous regions with putative causative disease genes was done by high-density SNP-array genotyping, followed by segregation analysis of the family members. Two distinct phenotypes of retinal dystrophy, Leber congenital amaurosis and Stargardt disease were present in the family. In the family, four patients with Leber congenital amaurosis were homozygous for a novel c.2557C>T (p.Q853X) mutation in the CRB1 gene, while of two cases with Stargardt disease, one was homozygous for c.5461-10T>C in the ABCA4 gene and another was carrier of the same mutation and a novel ABCA4 mutation c.4773+3A>G. Sequence analysis of the entire ABCA4 gene in patients with Stargardt disease revealed complex alleles with additional sequence variants, which were evaluated by bioinformatics tools. In conclusion, presence of different genetic mechanisms resulting in variable phenotype within the family is not rare and can challenge molecular geneticists, ophthalmologists and genetic counsellors.

Place, publisher, year, edition, pages
Nature Publishing Group, 2013
Keywords
CRB1, ABCA4, SNP-array, Stargardt disease, Leber congenital amaurosis
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-82275 (URN)10.1038/ejhg.2013.23 (DOI)000325861500015 ()23443024 (PubMedID)
Available from: 2013-10-29 Created: 2013-10-29 Last updated: 2018-06-08Bibliographically approved
Reinis, A., Golovleva, I., Köhn, L. & Sandgren, O. (2013). Ocular phenotype of CORD5, an autosomal dominant retinal dystrophy associated with PITPNM3 p.Q626H mutation. Acta Ophthalmologica, 91(3), 259-266
Open this publication in new window or tab >>Ocular phenotype of CORD5, an autosomal dominant retinal dystrophy associated with PITPNM3 p.Q626H mutation
2013 (English)In: Acta Ophthalmologica, ISSN 1755-375X, E-ISSN 1755-3768, Vol. 91, no 3, p. 259-266Article in journal (Refereed) Published
Abstract [en]

Purpose: To describe in detail the phenotype of CORD5 in two families segregating a mutation c.1878G > C (p.Q626H) in the PITPNM3 gene. Methods: The study included 35 individuals from two different families of Swedish origin, all heterozygous for a PITPNM3 p.Q626H mutation. All participants underwent ophthalmological examination including kinetic perimetry, and in selected cases adaptometry, colour vision tests and optical coherence tomography (OCT). Electrophysiological studies were also performed. In some cases, the data were obtained from medical records. Results: The majority of patients showed subnormal visual acuity and light sensitivity from childhood. Early signs of macular degeneration were also observed. There was a progressive decrease in visual acuity leading to legal blindness in early adulthood. Electrophysiological testing showed a progressive loss of photoreceptor function restricted mainly to the cones. OCT revealed decreased macular thickness with flattened and enlarged fovea. Conclusion: Our observations of the PITPNM3 p.Q626H mutation carriers confirm that CORD5 is a disease not to mix with other retinal degenerations mapped to 17p13. The results of our clinical evaluation so far indicate that CORD5 is characterized by predominant cone dysfunction without signs of general involvement of the retinal pigment epithelium. The rod system also seems to be unaffected. In this sense, CORD5 is different from other autosomal dominant CORDs where rod involvement is present to some degree in a late phase of the disease. Some intra-and inter-familial differences regarding the severity of the clinical picture were observed.

Keywords
cone-rod dystrophy, CORD5, electroretinography, mutation, optical coherence tomography, PITPNM3
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-71590 (URN)10.1111/j.1755-3768.2011.02381.x (DOI)000317983000032 ()
Available from: 2013-06-05 Created: 2013-06-04 Last updated: 2018-06-08Bibliographically approved
Golovleva, I., Köhn, L., Burstedt, M., Daiger, S. & Sandgren, O. (2010). Mutation spectra in autosomal dominant and recessive retinitis pigmentosa in northern sweden.. Advances in Experimental Medicine and Biology, 664, 255-262
Open this publication in new window or tab >>Mutation spectra in autosomal dominant and recessive retinitis pigmentosa in northern sweden.
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2010 (English)In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 664, p. 255-262Article in journal (Refereed) Published
Abstract [en]

Retinal degenerations represent a heterogeneous group of disorders affecting the function of the retina. The frequency of retinitis pigmentosa (RP) is 1/3500 worldwide, however, in northern Sweden it is 1/2000 due to limited migration and a 'founder' effect. In this study we identified genetic mechanisms underlying autosomal dominant and recessive RP present in northern Sweden. Several novel mutations unique for this region were found. In an autosomal recessive form of RP, Bothnia dystrophy caused by mutations in the RLBP1 gene, bi-allelic mutations R234W, M226K and compound heterozygosity, M226K+R234W was detected.In dominant form of RP mapped to 19q13.42 a 59 kb genomic deletion including the PRPF31 and three other genes was found.These data provide additional information on the molecular mechanisms of RP evolvement and in the future might be useful in development of therapeutic strategies. Identification of the disease-causing mutations allowed introducing molecular genetic testing of the patients and their families into the clinical practice.

Keywords
retinitis pigmentosa
National Category
Ophthalmology
Research subject
Ophtalmology
Identifiers
urn:nbn:se:umu:diva-34174 (URN)10.1007/978-1-4419-1399-9_29 (DOI)000277660900029 ()20238024 (PubMedID)744 (Local ID)744 (Archive number)744 (OAI)
Available from: 2010-05-18 Created: 2010-05-18 Last updated: 2018-06-08Bibliographically approved
Köhn, L., Kohl, S., Bowne, S. J., Sullivan, L. S., Kellner, U., Daiger, S. P., . . . Golovleva, I. (2010). PITPNM3 is an uncommon cause of cone and cone-rod dystrophies.. Ophthalmic Genetics, 31(3), 139-140
Open this publication in new window or tab >>PITPNM3 is an uncommon cause of cone and cone-rod dystrophies.
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2010 (English)In: Ophthalmic Genetics, ISSN 1381-6810, E-ISSN 1744-5094, Vol. 31, no 3, p. 139-140Article in journal (Refereed) Published
Abstract [en]

The first mutation in PITPNM3, a human homologue of the Drosophila retinal degeneration (rdgB not not) gene was reported in two large Swedish families with autosomal dominant cone dystrophy. To establish the global impact that PITPNM3 has on retinal degenerations we screened 163 patients from Denmark, Germany, the UK, and USA. Four sequence variants, two missence mutations and two intronic changes were identified in the screen. Thus, mutations in PITPNM3 do not appear to be a major cause of cone or cone-rod dystrophy.

Place, publisher, year, edition, pages
Informa Healthcare, 2010
Keywords
PITPNM3, mutation, cone dystrophy
National Category
Ophthalmology Medical Genetics
Research subject
Ophtalmology; Clinical Genetics
Identifiers
urn:nbn:se:umu:diva-35499 (URN)10.3109/13816810.2010.486776 (DOI)000282248100007 ()20590364 (PubMedID)744 (Local ID)744 (Archive number)744 (OAI)
Available from: 2010-08-20 Created: 2010-08-20 Last updated: 2018-06-08Bibliographically approved
Kawaji, T., Ando, Y., Ando, E., Sandgren, O., Suhr, O. B. & Tanihara, H. (2010). Transthyretin-related vitreous amyloidosis in different endemic areas.. Amyloid: Journal of Protein Folding Disorders, 17(3-4), 105-108
Open this publication in new window or tab >>Transthyretin-related vitreous amyloidosis in different endemic areas.
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2010 (English)In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 17, no 3-4, p. 105-108Article in journal (Refereed) Published
Abstract [en]

Background: to investigate the vitreous opacity in patients with familial amyloidotic polyneuropathy (FAP) in two major endemic areas, Japan and Sweden. Methods: we obtained clinical data for 90 patients with vitreous opacity that was associated with FAP amyloidogenic transthyretin (ATTR) Val30Met; 18 Japanese patients and 72 Swedish patients. We reviewed medical records at Kumamoto University Hospital in Japan and Umeå University Hospital in Sweden. We evaluated the characteristics of the patients, systemic and ocular histories, clinical findings and treatment. RESULTS: swedish patients were significantly older at the onset of vitreous opacity (mean age 67.8 years) than were Japanese patients (47.6 years). A similar age difference was found for the onset of polyneuropathy. In addition, Swedish patients without polyneuropathy were significantly older (74.1 years) at the onset of vitreous opacity than those with polyneuropathy (64.6 years). A significant difference in the occurrence of vitreous opacity as the only manifestation of FAP was seen for Swedish patients (35%) compared with Japanese patients (6%). CONCLUSIONS: swedish FAP ATTR Val30Met patients appeared to develop vitreous opacity later and more frequently compared with Japanese patients.

Place, publisher, year, edition, pages
Informa Healthcare, 2010
Keywords
Familial amyloidotic polyneuropathy, ocular manifestations, vitreous opacity, genetic heterogeneity, transthyretin
National Category
Medical and Health Sciences
Research subject
Medicine; Ophtalmology
Identifiers
urn:nbn:se:umu:diva-42571 (URN)10.3109/13506129.2010.527068 (DOI)000284268400003 ()21077797 (PubMedID)
Available from: 2011-04-11 Created: 2011-04-11 Last updated: 2018-06-08Bibliographically approved
Köhn, L., Bowne, S. J., Daiger, S. P., Burstedt, M. S., Kadzhaev, K., Sandgren, O. & Golovleva, I. (2009). Breakpoint characterization of a novel ~59 kb genomic deletion on 19q13.42 in autosomal dominant retinitis pigmentosa with reduced penetrance. European Journal of Human Genetics, 17(5), 651-655
Open this publication in new window or tab >>Breakpoint characterization of a novel ~59 kb genomic deletion on 19q13.42 in autosomal dominant retinitis pigmentosa with reduced penetrance
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2009 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 17, no 5, p. 651-655Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to identify and characterize the underlying molecular mechanisms in autosomal-dominant retinitis pigmentosa (adRP) with incomplete penetrance in two Swedish families. An extended genealogical study and haplotype analysis indicated a common origin. Mutation identification was carried out by multiplex ligation-dependent probe amplification (MLPA) and sequencing. Clinical examinations of adRP families including electroretinography revealed obligate gene carriers without abnormalities, which indicated incomplete penetrance. Linkage analysis resulted in mapping of the disease locus to 19q13.42 (RP11). Sequence analyses did not reveal any mutations segregating with the disease in eight genes including PRPF31. Subsequent MLPA detected a large genomic deletion of 11 exons in the PRPF31 gene and, additionally, three genes upstream of the PRPF31. Breakpoints occurred in intron 11 of PRPF31 and in LOC441864, 'similar to osteoclast-associated receptor isoform 5.' An almost 59 kb deletion segregated with the disease in all affected individuals and was present in several asymptomatic family members but not in 20 simplex RP cases or 94 healthy controls tested by allele-specific PCR. A large genomic deletion resulting in almost entire loss of PRPF31 and three additional genes identified as the cause of adRP in two Swedish families provide an additional evidence that mechanism of the disease evolvement is haploinsufficiency. Identification of the deletion breakpoints allowed development of a simple tool for molecular testing of this genetic subtype of adRP.

Place, publisher, year, edition, pages
Nature publishing group, 2009
Keywords
PRPF31; retinitis pigmentosa; RP11; deletion; haploinsufficiency
National Category
Medical Genetics
Research subject
Genetics
Identifiers
urn:nbn:se:umu:diva-26979 (URN)10.1038/ejhg.2008.223 (DOI)
Available from: 2009-11-05 Created: 2009-11-05 Last updated: 2018-06-08Bibliographically approved
Köhn, L., Bowne, S. J., S Sullivan, L., Daiger, S. P., Burstedt, M. S., Kadzhaev, K., . . . Golovleva, I. (2009). Breakpoint characterization of a novel approximately 59 kb genomic deletion on 19q13.42 in autosomal-dominant retinitis pigmentosa with incomplete penetrance.. European Journal of Human Genetics, 17(5), 651-655
Open this publication in new window or tab >>Breakpoint characterization of a novel approximately 59 kb genomic deletion on 19q13.42 in autosomal-dominant retinitis pigmentosa with incomplete penetrance.
Show others...
2009 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 17, no 5, p. 651-655Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to identify and characterize the underlying molecular mechanisms in autosomal-dominant retinitis pigmentosa (adRP) with incomplete penetrance in two Swedish families. An extended genealogical study and haplotype analysis indicated a common origin. Mutation identification was carried out by multiplex ligation-dependent probe amplification (MLPA) and sequencing. Clinical examinations of adRP families including electroretinography revealed obligate gene carriers without abnormalities, which indicated incomplete penetrance. Linkage analysis resulted in mapping of the disease locus to 19q13.42 (RP11). Sequence analyses did not reveal any mutations segregating with the disease in eight genes including PRPF31. Subsequent MLPA detected a large genomic deletion of 11 exons in the PRPF31 gene and, additionally, three genes upstream of the PRPF31. Breakpoints occurred in intron 11 of PRPF31 and in LOC441864, 'similar to osteoclast-associated receptor isoform 5.' An almost 59 kb deletion segregated with the disease in all affected individuals and was present in several asymptomatic family members but not in 20 simplex RP cases or 94 healthy controls tested by allele-specific PCR. A large genomic deletion resulting in almost entire loss of PRPF31 and three additional genes identified as the cause of adRP in two Swedish families provide an additional evidence that mechanism of the disease evolvement is haploinsufficiency. Identification of the deletion breakpoints allowed development of a simple tool for molecular testing of this genetic subtype of adRP.

Keywords
PRPF31, retinitis pigmentosa, RP11, deletion, haploinsufficiency
Identifiers
urn:nbn:se:umu:diva-36998 (URN)10.1038/ejhg.2008.223 (DOI)19050727 (PubMedID)
Available from: 2010-10-14 Created: 2010-10-14 Last updated: 2018-06-08Bibliographically approved
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