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  • 1.
    Blomstedt, Patric
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Hariz, Marwan I
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Tisch, Stephen
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Bergenheim, Tommy A
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    A family with a hereditary form of torsion dystonia from northern Sweden treated with bilateral pallidal deep brain stimulation2009In: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 24, no 16, p. 2415-2419Article in journal (Refereed)
    Abstract [en]

    To evaluate pallidal DBS in a non-DYT1 form of hereditary dystonia. We present the results of pallidal DBS in a family with non-DYT1 dystonia where DYT5 to 17 was excluded. The dystonia is following an autosomal dominant pattern. Ten members had definite dystonia and five had dystonia with minor symptoms. Four patients received bilateral pallidal DBS. Mean age was 47 years. The patients were evaluated before surgery, and "on" stimulation after a mean of 2.5 years (range 1-3) using the Burke-Fahn-Marsden scale (BFM). Mean BFM score decreased by 79 % on stimulation, from 42.5 +/- 24 to 9 +/- 6.5 at the last evaluation. Cervical involvement improved by 89%. The 2 patients with oromandibular dystonia and blepharospasm demonstrated a reduction of 95% regarding these symptoms. The present study confirms the effectiveness of pallidal DBS in a new family with hereditary primary segmental and generalized dystonia.

  • 2.
    Einarsdottir, Elisabet
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Carlsson, Anna
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Minde, Jan
    Toolanen, Göran
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Orthopaedics.
    Svensson, Olle
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Orthopaedics.
    Solders, Göran
    Holmgren, Gösta
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception.2004In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 13, no 8, p. 799-805Article in journal (Refereed)
    Abstract [en]

    Identification of genes associated with pain insensitivity syndromes can increase the understanding of the pathways involved in pain and contribute to the understanding of how sensory pathways relate to other neurological functions. In this report we describe the mapping and identification of the gene responsible for loss of deep pain perception in a large family from northern Sweden. The loss of pain perception in this family is characterized by impairment in the sensing of deep pain and temperature but with normal mental abilities and with most other neurological responses intact. A severe reduction of unmyelinated nerve fibers and a moderate loss of thin myelinated nerve fibers are observed in the patients. Thus the cases in this study fall into the class of patients with loss of pain perception with underlying peripheral neuropathy. Clinically they best fit into HSAN V. Using a model of recessive inheritance we identified an 8.3 Mb region on chromosome 1p11.2-p13.2 shared by the affected individuals in the family. Analysis of functional candidate genes in the disease critical region revealed a mutation in the coding region of the nerve growth-factor beta (NGFB) gene specific for the disease haplotype. This NGF mutation seems to separate the effects of NGF involved in development of central nervous system functions such as mental abilities, from those involved in peripheral pain pathways. This mutation could therefore potentially provide an important tool to study different roles of NGF, and of pain control.

  • 3.
    Einarsdottir, Elisabet
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Löfgren-Burström, Anna
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Unit for Genome Research, Umeå University.
    Haraldsson, Susann
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Unit for Genome Research, Umeå University.
    Nilsson-Ardnor, Sofie
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Unit for Genome Research, Umeå University.
    Penha-Goncalves, Carlos
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Gulbenkian Institute for Science, Oeiras, Portugal.
    Lind, Lisbet
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Unit for Genome Research, Umeå University.
    Holmgren, Gösta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Asplund, Kjell
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Unit for Genome Research.
    The CTLA4 region as a general autoimmunity factor: an extended pedigree provides evidence for synergy with the HLA locus in the etiology of type 1 diabetes mellitus, Hashimoto's thyroiditis and Graves' disease2003In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 11, no 1, p. 81-84Article in journal (Refereed)
    Abstract [en]

    We have identified a large family in the northern part of Sweden with multiple cases of autoimmune diseases, namely type 1 diabetes (T1D), Graves' disease (GD) and Hashimoto's thyroiditis (HT). The family members affected by any of these diseases share a region of 2.4 Mb that comprises among others the CTLA4 gene. We determined that all affected members of the family shared the HLA susceptibility haplotype (DR4-DQA1*0301-DQB1*0302). Analysis of genetic interaction conditioning for HLA haplotype provided strong evidence that the critical region which includes the CTLA4 gene acts together with the HLA locus on the etiology of disease (lodscore 4.20 (theta=0.0). The study of this family allowed us to: (1) reinforce a number of reports on linkage and association of the CTLA4 region to T1D and AITD; (2) demonstrate that a single haplotypic variant in this region constitutes an etiological factor to disease susceptibility in T1D, GD and HT; (3) reveal a strong genetic interaction of the CTLA4 and HLA loci in the genetic architecture of autoimmune disease; (4) emphasise the value of large pedigrees drawn from isolated populations as tools to single out the effect of individual loci in the etiology of complex diseases.

  • 4. Jonasson, Jenni
    et al.
    Ström, Anna-Lena
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hart, Patricia
    Brännström, Thomas
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Holmberg, Monica
    Expression of ataxin-7 in CNS and non-CNS tissue of normal and SCA7 individuals2002In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 104, no 1, p. 29-37Article in journal (Refereed)
    Abstract [en]

    Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder primarily affecting the cerebellum, brain stem and retina. The disease is caused by an expanded polyglutamine tract in the protein ataxin-7. In this study we analyzed the expression pattern of ataxin-7 in CNS and non-CNS tissue from three SCA7 patients and age-matched controls. SCA7 is a rare autosomal dominant disorder, limiting the number of patients available for analysis. We therefore compiled data on ataxin-7 expression from all SCA7 patients (n=5) and controls (n=7) published to date, and compared with the results obtained in this study. Expression of ataxin-7 was found in neurons throughout the CNS and was highly abundant in Purkinje cells of the cerebellum, in regions of the hippocampus and in cerebral cortex. Ataxin-7 expression was not restricted to regions of pathology, and there were no apparent regional differences in ataxin-7 expression patterns between patients and controls. The subcellular distribution of ataxin-7 was primarily nuclear in all brain regions studied. In cerebellar Purkinje cells, however, differences in subcellular distribution of ataxin-7 were observed between patients and controls of different ages. Here we provide an increased understanding of the distribution of ataxin-7, and the possible implication of subcellular localization of this protein on disease pathology is discussed.

  • 5.
    Jonsson, Frida
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Boström, Ida Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Österman, Lennart
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Sandgren, Ola
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Burstedt, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    ATP-binding cassette subfamily A, member 4 intronic variants c.4773+3A > G and c.5461-10T > C cause Stargardt disease due to defective splicing2018In: Acta Ophthalmologica, ISSN 1755-375X, E-ISSN 1755-3768, Vol. 96, no 7, p. 737-743Article in journal (Refereed)
    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.

  • 6.
    Larsson, Elin
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Fahey, Mark S.
    Watson, Judy J.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Dawbarn, David
    Allen, Shelley J.
    Purification and Characterization of the Nerve Growth Factor R221W mutant causing Insensitivity to PainManuscript (preprint) (Other academic)
    Abstract [en]

     

    We have previously identified a homozygous missense (R221W) mutation in the NGFβ gene which causes insensitivity to pain in patients. The mutation impairs the secretion of NGF and the majority of the protein accumulates as proNGF. NGF mediates its function by binding and activating the TrkA and p75 receptors and is important for the survival of the sensory and sympathetic neurons as well as the cholinergic neurons of the basal forebrain. However, the R221W mutation seems to discriminate between these types of neurons as it is the sensory neurons that are mainly affected in the patients. A second human NGFβ mutation causes a more severe form of pain insensitivity with additional anhidrosis and cognitive dysfunctions in affected patients which is also seen in patients with mutations in the gene encoding the TrkA receptor. Because R221W NGF cause a less severe phenotype we hypothesised that the mutation mainly affects the p75 interaction which is also strengthened by the fact that the substitution is located in a region known to interact with p75. In this report, we show that R221W NGF is able to bind and activate TrkA at a level comparable to wild-type NGF in cells stably expressing TrkA while the activation of the downstream target ERK1/2 is impaired in cells that co-express TrkA and p75. We also describe the effects of the mutation in terms of expression and purification properties from E.coli which indicate the likelihood that eukaryotic folding machinery is needed for correct folding of R221W NGF.

  • 7.
    Larsson, Elin
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Kuma, Regina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Norberg, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Minde, Jan
    Department of Orthopedics, Gällivare Hospital, Gällivare, Sweden.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Nerve growth factor R221W responsible for insensitivity to pain is defectively processed and accumulates as proNGF2009In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 33, no 2, p. 221-228Article in journal (Refereed)
    Abstract [en]

    We have previously identified a homozygous missense (R221W) mutation in the NGFB gene in patients with loss of deep pain perception. NGF is important not only for the survival of sensory neurons but also for the sympathetic neurons and cholinergic neurons of the basal forebrain; however, it is the sensory neurons that are mainly affected in patients with mutant NGFB. In this report, we describe the effects of the mutation on the function of NGF protein and the molecular mechanisms that may underlie the pain insensitivity phenotype in these patients. We show that the mutant NGF has lost its ability to mediate differentiation of PC12 cells into a neuron-like phenotype. We also show that the inability of PC12 cells to differentiate is due to a markedly reduced secretion of mature R221W NGF. The R221W NGF is found mainly as proNGF, in contrast to wild-type NGF which is predominantly in the mature form in both undifferentiated and differentiated PC12 cells. The reduction in numbers of sensory fibers observed in the patients is therefore probably due to loss of trophic support as a result of drastically reduced secretion of NGF from the target organs. Taken together, these data show a clear decrease in the availability of mutant mature NGF and also an accumulation of proNGF in both neuronal and non-neuronal cells. The differential loss of NGF-dependent neurons in these patients, mainly affecting sensory neurons, may depend on differences in the roles of mature NGF and proNGF in different cells and tissues.

  • 8.
    Minde, Jan
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Andersson, T
    Department of Clinical Neuroscience Section of Neurophysiology, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden .
    Fulford, M
    Department of Internal Medicine, Gällivare Hospital, Gällivare, Sweden.
    Aguirre, M
    Department of Clinical Neuroscience Section of Neurophysiology, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden .
    Nennesmo, I
    Department of Pathology, Karolinska University Hospital, Stockholm, Sweden.
    Remahl, I Nilsson
    Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
    Svensson, Olle
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Toolanen, Göran
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Solders, G
    Department of Clinical Neuroscience Section of Neurophysiology, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden .
    A novel NGFB point mutation: a phenotype study of heterozygous patients2009In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 80, no 2, p. 188-195Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: A family with neurological findings similar to hereditary sensory and autonomic neuropathy type V having a point mutation in the nerve growth factor beta (NGFB) gene was recently described. The homozygous genotype gives disabling symptoms. The purpose of the present study was to evaluate the symptoms in heterozygous patients. METHODS: 26 patients heterozygous for the NGFB mutation (12 men, mean age 50 (13-90) years) were examined clinically and answered a health status questionnaire, including the Michigan Neuropathy Screening Instrument (MNSI). 28 relatives (15 men, mean age 44 (15-86) years) without the mutation served as controls in the clinical examination part. 23 of the heterozygotes were examined neurophysiologically and six heterozygous patients underwent a sural nerve biopsy. RESULTS: The heterozygous phenotype ranged from eight patients with Charcot arthropathy starting in adult age and associated with variable symptoms of neuropathy but without complete insensitivity to pain, anhidrosis or mental retardation, to 10 symptom free patients. There was no difference in MNSI between the young heterozygous cases (<55 years old) and the controls. Six of 23 heterozygous patients had impaired cutaneous thermal perception and 11 of 23 had signs of carpal tunnel syndrome. Sural nerve biopsies showed a moderate reduction of both small myelinated (Adelta) and unmyelinated (C) fibres. No apparent correlation of small fibre reduction to symptoms was found. CONCLUSIONS: The NGFB mutation in its heterozygous form results in a milder disease than in homozygotes, with a variable clinical picture, ranging from asymptomatic cases to those with Charcot arthropathy appearing in adult age. Particularly age, but perhaps lifestyle factors also, may influence the development of clinical polyneuropathy.

  • 9.
    Minde, Jan
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Fulford, M
    Andersson, T
    Aguierre, M
    Nennesmo, I
    Nilsson-Remahl, I
    Svensson, O
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Toolanen, G
    Solders, G
    HSAN V, a phenotype study of patients heterozygous for the NGFß-mutationManuscript (Other academic)
  • 10.
    Minde, Jan
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Orthopaedics.
    Svensson, Olle
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Orthopaedics.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Solders, Göran
    Toolanen, Göran
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Orthopaedics.
    Orthopedic aspects of familial insensitivity to pain due to a novel nerve growth factor beta mutation.2006In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 77, no 2, p. 198-202Article in journal (Refereed)
  • 11.
    Norberg, Anna
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Exclusion of the juvenile myoclonic epilepsy gene EFHC1 as the cause of migraine on chromosome 6, but association to two rare polymorphisms in MEP1A and RHAG.2006In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 396, no 2, p. 137-142Article in journal (Refereed)
  • 12.
    Nordin, Angelica
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Larsson, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    The defective splicing caused by the ISCU intron mutation in patients with myopathy with lactic acidosis is repressed by PTBP1 but can be de-repressed by IGF2BP12012In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 33, no 3, p. 467-470Article in journal (Refereed)
    Abstract [en]

    Hereditary myopathy with lactic acidosis (HML) is caused by an intron mutation in the iron-sulfur cluster assembly gene ISCU which leads to the activation of cryptic splice sites and the retention of part of intron 4. This incorrect splicing is more pronounced in muscle than in other tissues, resulting in a muscle-specific phenotype. In this study, we identified five nuclear factors that interact with the sequence harboring the mutation and analyzed their effect on the splicing of the ISCU gene. The identification revealed three splicing factors, SFRS14, RBM39 and PTBP1, and two additional RNA binding factors, matrin 3 (MATR3) and IGF2BP1. IGF2BP1 showed a preference for the mutant sequence, whereas the other factors showed similar affinity for both sequences. PTBP1 was found to repress the defective splicing of ISCU, resulting in a drastic loss of mutant transcripts. In contrast, IGF2BP1 and RBM39 shifted the splicing ratio toward the incorrect splice form.

  • 13.
    Nordin, Angelica
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Larsson, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Tissue-specific splicing of ISCU results in a skeletal muscle phenotype in myopathy with lactic acidosis, while complete loss of ISCU results in early embryonic death in mice2011In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 129, no 4, p. 371-378Article in journal (Refereed)
    Abstract [en]

    Hereditary myopathy with lactic acidosis (HML) is caused by an intron mutation in the iron-sulphur cluster assembly gene (ISCU) leading to incorporation of intron sequence into the mRNA. This results in a deficiency of Fe-S cluster proteins, affecting the TCA cycle and the respiratory chain. The proteins involved in the Fe-S machinery are evolutionary conserved and shown to be fundamental in all organisms examined. ISCU is expressed at high levels in numerous tissues in mammals, including high metabolic tissues like the heart, suggesting that a drastic mutation in the ISCU gene would be damaging to all energy-demanding organs. In spite of this, the symptoms in patients with HML are restricted to skeletal muscle, and it has been proposed that splicing events may contribute to the muscle specificity. In this study we confirm that a striking difference in the splicing pattern of mutant ISCU exists between different tissues. The highest level of incorrectly spliced ISCU mRNA was found in skeletal muscle, while the normal splice form predominated in patient heart. The splicing differences were also reflected at a functional level, where loss of Fe-S cluster carrying enzymes and accumulation of iron were present in muscle, but absent in other tissues. We also show that complete loss of ISCU in mice results in early embryonic death. The mice data confirm a fundamental role for ISCU in mammals and further support tissue-specific splicing as the major mechanism limiting the phenotype to skeletal muscle in HML.

  • 14.
    Norgren, Nina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mattson, Emma
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    A high-penetrance form of late-onset torsion dystonia maps to a novel locus (DYT21) on chromosome 2q14.3-q21.32011In: Neurogenetics, ISSN 1364-6745, E-ISSN 1364-6753, Vol. 12, no 2, p. 137-143Article in journal (Refereed)
    Abstract [en]

    The primary dystonias are a genetically heterogeneous group of disorders that can be subdivided in pure dystonias, dystonia-plus syndromes, and paroxymal dystonia. Four pure autosomal dominant dystonia loci have been mapped to date, DYT1, 6, 7, and 13, with varying penetrance. We report the mapping of a novel locus for a late-onset form of pure torsion dystonia in a family from northern Sweden. The disease is inherited in an autosomal dominant manner with a penetrance that may be as high as 90%. The torsion dystonia locus in this family was mapped to chromosome 2q14.3-q21.3 using an Illumina linkage panel. We also confirmed the linkage, using ten tightly linked microsatellite markers in the region, giving a maximum LOD score of 5.59 for marker D2S1260. The disease-critical region is 3.6-8.9 Mb depending on the disease status of one individual carrying a centromeric recombination. Mutational analysis was performed on 22 genes in the disease-critical region, including all known and hypothetical genes in the smaller, 3.6-Mb region, but no disease-specific mutations were identified. Copy number variation analysis of the region did not reveal any deletions or duplications. In order to increase the chances of finding the disease gene, fine-mapping may be necessary to decrease the region of interest. This report will hopefully result in the identification of additional dystonia families with linkage to the same locus, and thereby, refinement of the disease critical region.

  • 15.
    Olsson, Angelica
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lind, Lisbet
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Myopathy with lactic acidosis is linked to chromosome 12q23.3-24.11 and caused by an intron mutation in the ISCU gene resulting in a splicing defect2008In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 17, no 11, p. 1666-1672Article in journal (Refereed)
    Abstract [en]

    We describe the mapping and identification of the gene for hereditary myopathy with lactic acidosis (HML). HML is characterized by low physical performance, resulting in physical exertion that causes early exhaustion, dyspnoea and palpitations. Using an autosomal recessive mode of inheritance, we mapped the trait to chromosome 12q23.3-24.11, with a maximum lod score of 5.26. The 1.6-Mb disease-critical region contained one obvious candidate gene-ISCU-specifying a protein involved in iron-sulphur cluster assembly. IscU is produced in two isoforms; one cytosolic and one mitochondrial, coded for by different splice variants of the ISCU gene. Mutational analysis of all exon and intron sequences as well as 1000 bp of the promoter of the ISCU gene revealed one intron mutation that was specific for the disease haplotype. The mutation is located in a region with homology to the interferon-stimulated response element (ISRE), but we could not see any effect of the mutation on expression levels in vitro or in vivo. We did, however, observe a drastic difference in the splicing pattern between patients and controls. In controls the mRNA was, as expected, mainly in the mitochondrial form, while in the patients a larger mRNA transcript was predominant. Sequencing of the product revealed that the mutation activates cryptic splice sites in intron 5 resulting in aberrant mRNA containing 100 bp of the intron. To conclude, our data strongly suggest that an intron mutation in the ISCU gene, leading to incorrectly spliced mRNA, is the cause of myopathy with lactic acidosis in this family.

  • 16.
    Rawcliffe, Denise F. R.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Johansson, Malin
    Österman, Lennart
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    MBNL1 and RBM39 can activate the incorrect splicing of ISCU and the aberrant transcript is a target for nonsense-mediated decayManuscript (preprint) (Other academic)
  • 17.
    Rawcliffe, Denise F. R.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Österman, Lennart
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lindsten, Hans
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience, Umeå University Hospital, Umeå, Sweden .
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    The High Level of Aberrant Splicing of ISCU in Slow-Twitch Muscle May Involve the Splicing Factor SRSF32016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, article id e0165453Article in journal (Refereed)
    Abstract [en]

    Hereditary myopathy with lactic acidosis (HML) is an autosomal recessive disease caused by an intronic one-base mutation in the iron-sulfur cluster assembly (ISCU) gene, resulting in aberrant splicing. The incorrectly spliced transcripts contain a 100 or 86 bp intron sequence encoding a non-functional ISCU protein, which leads to defects in several Fe-S containing proteins in the respiratory chain and the TCA cycle. The symptoms in HML are restricted to skeletal muscle, and it has been proposed that this effect is due to higher levels of incorrectly spliced ISCU in skeletal muscle compared with other energy-demanding tissues. In this study, we confirm that skeletal muscle contains the highest levels of incorrect ISCU splice variants compared with heart, brain, liver and kidney using a transgenic mouse model expressing human HML mutated ISCU. We also show that incorrect splicing occurs to a significantly higher extent in the slow-twitch soleus muscle compared with the gastrocnemius and quadriceps. The splicing factor serine/arginine-rich splicing factor 3 (SRSF3) was identified as a potential candidate for the slow fiber specific regulation of ISCU splicing since this factor was expressed at higher levels in the soleus compared to the gastrocnemius and quadriceps. We identified an interaction between SRSF3 and the ISCU transcript, and by overexpressing SRSF3 in human myoblasts we observed increased levels of incorrectly spliced ISCU, while knockdown of SRSF3 resulted in decreased levels. We therefore suggest that SRSF3 may participate in the regulation of the incorrect splicing of mutant ISCU and may, at least partially, explain the muscle-specific symptoms of HML.

  • 18.
    Rawcliffe, Denise F. R.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Österman, Lennart
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Nordin, Angelica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    PTBP1 acts as a dominant repressor of the aberrant tissue-specific splicing of ISCU in hereditary myopathy with lactic acidosis2018In: Molecular Genetics & Genomic Medicine, ISSN 2324-9269, Vol. 6, no 6, p. 887-897Article in journal (Refereed)
    Abstract [en]

    Background: Hereditary myopathy with lactic acidosis (HML) is an autosomal recessive disease caused by an intron mutation in the iron-sulfur cluster assembly (ISCU) gene. The mutation results in aberrant splicing, where part of the intron is retained in the final mRNA transcript, giving rise to a truncated nonfunctional ISCU protein. Using an ISCU mini-gene system, we have previously shown that PTBP1 can act as a repressor of the mis-splicing of ISCU, where overexpression of PTBP1 resulted in a decrease of the incorrect splicing. In this study, we wanted to, in more detail, analyze the role of PTBP1 in the regulation of endogenous ISCU mis-splicing.

    Methods: Overexpression and knockdown of PTBP1 was performed in myoblasts from two HML patients and a healthy control. Quantification of ISCU mis-splicing was done by qRTPCR. Biotinylated ISCU RNA, representing wildtype and mutant intron sequence, was used in a pull-down assay with nuclear extracts from myoblasts. Levels of PTBP1 in human cell lines and mice tissues were analyzed by qRTPCR and western blot.

    Results: PTBP1 overexpression in HML patient myoblasts resulted in a substantial decrease of ISCU mis-splicing while knockdown of PTBP1 resulted in a drastic increase. The effect could be observed in both patient and control myoblasts. We could also show that PTBP1 interacts with both the mutant and wild-type ISCU intron sequence, but with a higher affinity to the mutant sequence. Furthermore, low levels of PTBP1 among examined mouse tissues correlated with high levels of incorrect splicing of ISCU.

    Conclusion: Our results show that PTBP1 acts as a dominant repressor of ISCU mis-splicing. We also show an inverse correlation between the levels of PTBP1 and ISCU mis-splicing, suggesting that the high level of mis-splicing in the skeletal muscle is primarily due to the low levels of PTBP1.

  • 19.
    Ström, Anna-Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neurophysiology.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    A role for both wild-type and expanded ataxin-7 in transcriptional regulation2005In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 20, no 3, p. 646-655Article in journal (Refereed)
    Abstract [en]

    Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease primarily affecting the brainstem, retina and Purkinje cells of the cerebellum. The disease is caused by a polyglutamine expansion in ataxin-7, a protein found in two complexes TFTC and STAGA, involved in transcriptional regulation. Transcriptional dysregulation has been implicated in the pathology of several polyglutamine diseases. In this paper, we analyzed the effect of both wild-type and expanded ataxin-7 on transcription driven by the co-activator CBP and the Purkinje cell expressed nuclear receptor RORα1. We could show that transcription mediated by both CBP and RORα1 was repressed by expanded ataxin-7. Interestingly, repression of transcription could also be observed with wild-type full-length ataxin-7, not only on CBP- and RORα1-mediated transcription, but also on basal transcription. The repression could be counteracted by inhibition of deacetylation, suggesting that ataxin-7 may act as a repressor of transcription by inhibiting the acetylation activity of TFTC and STAGA.

  • 20.
    Ström, Anna-Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Identification and characterization of Spinocerebellar Ataxia Type 7 (SCA7) isoform SCA7b in mice2005In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1731, no 3, p. 149-153Article in journal (Refereed)
    Abstract [en]

    Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease primarily affecting the cerebellum, brainstem and retina. The disease is caused by a polyglutamine expansion in ataxin-7, a protein with largely unknown function. To improve our knowledge of the expression and function of wild-type and expanded ataxin-7, we looked for alternative SCA7 transcripts in mice. We identified a murine SCA7 isoform (SCA7b) containing an uncharacterized exon homologous to the newly identified human exon 12b. Northern blot analysis revealed three exon 12b containing transcripts with molecular sizes of 7.5, 4.4 and 3.0 kb in mice. This contrasted with the situation in humans, where only one exon 12b-containing transcript was observed. Furthermore, Northern blot of the human 4.4 kb SCA7b isoform predominantly showed expression in the brain, while expression of both the murine 7.5-kb and the 4.4-kb transcripts were observed in several tissues including brain, heart, liver, kidney and testis. Quantitative real-time RT-PCR analysis revealed that in muscle and heart SCA7b is the predominant SCA7 isoform, while in brain equal levels of SCA7a and SCA7b was observed. Insertion of exon 12b into the murine SCA7 ORF resulted in a frame-shift that gave rise to an alternative ataxin-7 protein (ataxin-7b). The novel 58-amino acid C-terminus in ataxin-7b directed the protein to a more cytoplasmic location.

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