Browsing by Subject "DEFICIENCY"

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  • Vakkilainen, Svetlana; Taskinen, Mervi; Klemetti, Paula; Pukkala, Eero; Mäkitie, Outi (2019)
    Cartilage-hair hypoplasia (CHH) is a skeletal dysplasia with combined immunodeficiency, variable clinical course and increased risk of malignancy. Management of CHH is complicated by a paucity of long-term follow-up data, as well as knowledge on prognostic factors. We assessed clinical course and risk factors for mortality in a prospective cohort study of 80 patients with CHH recruited in 1985-1991 and followed up until 2016. For all patients we collected additional health information from health records and from the national Medical Databases and Cause-of-death Registry. The primary outcome was immunodeficiency-related death, including death from infections, lung disease and malignancy. Standardized mortality ratios (SMRs) were calculated using national mortality rates as reference. Half of the patients (57%, n = 46) manifested no symptoms of immunodeficiency during follow-up while 19% (n = 15) and 24% (n = 19) demonstrated symptoms of humoral or combined immunodeficiency, including six cases of adult-onset immunodeficiency. In a significant proportion of patients (17/79, 22%), clinical features of immunodeficiency progressed over time. Of the 15 patients with non-skin cancer, eight had no preceding clinical symptoms of immunodeficiency. Altogether 20 patients had deceased (SMR = 7.0, 95% CI = 4.3-11); most commonly from malignancy (n = 7, SMR = 10, 95% CI = 4.1-21) and lung disease (n = 4, SMR = 46, 95% CI = 9.5-130). Mortality associated with birth length below-4 standard deviation (compared to normal, SMR/SMR ratio = 5.4, 95% CI = 1.5-20), symptoms of combined immunodeficiency (compared to asymptomatic, SMR/SMR ratio= 3.9, 95% CI = 1.3-11), Hirschsprung disease (odds ratio (OR) 7.2, 95% CI = 1.04-55), pneumonia in the first year of life or recurrently in adulthood (OR = 7.6/19, 95% CI = 1.3-43/2.6-140) and autoimmunity in adulthood (OR = 39, 95% CI = 3.5-430). In conclusion, patients with CHH may develop adult-onset immunodeficiency or malignancy without preceding clinical symptoms of immune defect, warranting careful follow-up. Variable disease course and risk factors for mortality should be acknowledged.
  • Pikkarainen, Sampsa; Martelius, Timi; Ristimäki, Ari; Siitonen, Sanna; Seppänen, Mikko R. J.; Färkkilä, Martti (2019)
    OBJECTIVES: Common variable immunodeficiency (CVID) is associated with a spectrum of autoimmune complications. We studied the prevalence of gastrointestinal (GI) manifestations and infections in patients with CVID. METHODS: Complete clinical data of 132 Finnish patients with CVID (106 probable and 26 possible CVID) followed up between 2007 and 2016 were collected to a structured database. Data on endoscopies, histology, and laboratory studies were retrieved from patient files. RESULTS: Most common referral indications were diarrhea and/or weight loss (47%-67%). Patients with probable CVID had higher fecal calprotectin and a1-antitrypsin and lower blood vitamin B12 than patients with possible CVID. Gastroscopy and colonoscopy were done to 71 (67%) and 63 (59%) patients with probable CVID, respectively. Endoscopies showed that 15% of them had chronic active gastritis and 17% atrophic gastritis and 3% had gastric adenocarcinoma. A celiac sprue-like condition was found in 7 patients (10%), of whom 3 responded to a gluten-free diet. Colonoscopies demonstrated unspecific colitis (14%), ulcerative colitis (8%), microscopic colitis (10%), and Crohn's disease (2%). Colonic polyps were noted in30% of patients, and3% had lower GI malignancies. Thirty-five patients with CVID had bacterial or parasitic gastroenteritis; chronic norovirus was detected in 4 patients with probable CVID. Patients with GI inflammation had higher levels of fecal calprotectin and blood CD81 T lymphocytes but lower counts of CD191CD271 memory B cells and/or CD191 B cells. Immunophenotype with low B-cell counts was associated with higher fecal calprotectin levels. DISCUSSION: Patients with CVID had a high prevalence of GI manifestations and infections of the GI tract. GI inflammation was associated with a distinct immunophenotype and elevated fecal calprotectin.
  • Sofou, Kalliopi; De Coo, Irenaeus F. M.; Isohanni, Pirjo; Ostergaard, Elsebet; Naess, Karin; De Meirleir, Linda; Tzoulis, Charalampos; Uusimaa, Johanna; De Angst, Isabell B.; Lonnqvist, Tuula; Pihko, Helena; Mankinen, Katariina; Bindoff, Laurence A.; Tulinius, Mar; Darin, Niklas (2014)
  • Berger, Claudia; Heyne, Henrike O.; Heiland, Tina; Dommel, Sebastian; Hoefling, Corinna; Guiu-Jurado, Esther; Lorenz, Jana; Rossner, Steffen; Dannemann, Michael; Kelso, Janet; Kovacs, Peter; Blueher, Matthias; Kloeting, Nora (2021)
    The leptin receptor (Lepr) pathway is important for food intake regulation, energy expen-diture, and body weight. Mutations in leptin and the Lepr have been shown to cause early-onset severe obesity in mice and humans. In studies with C57BL/ 6NCrl mice, we found a mouse with extreme obesity. To identify a putative spontaneous new form of monogenic obesity, we performed backcross studies with this mouse followed by a quantitative trait locus (QTL) analysis and sequencing of the selected chro-mosomal QTL region. We thereby identified a novel Lepr mutation (C57BL/6N-Lepr(L536Hfs*6-1NKB)), which is located at chromosome 4, exon 11 within the CRH2-leptin-binding site. Compared with C57BL/6N mice, Lepr(L536Hfs*6) develop early onset obesity and their body weight exceeds that of Leprdb/db mice at an age of 30 weeks. Similar to Leprdb/db mice, the Lepr(L536Hfs*6) model is characterized by hyperphagia, obesity, lower energy expenditure and activity, hyperglycemia, and hyperinsulinemia compared with C57BL/6N mice. Crossing Leprdb/wt with Lepr(L536Hfs*6/wt) mice results in compound heterozygous Lepr(L536Hfs*6/db) mice, which develop even higher body weight and fat mass than both homozygous Lepr(db/db) and Lepr(L536Hfs*6) mice. Compound heterozygous Lepr deficiency affecting functionally different regions of the Lepr causes more severe obesity than the parental homozygous mutations.
  • GEMSTONE Working Grp 3 COST Action; Formosa, Melissa M.; Bergen, Dylan J. M.; Gregson, Celia L.; Mäkitie, Outi (2021)
    Genetic disorders of the skeleton encompass a diverse group of bone diseases differing in clinical characteristics, severity, incidence and molecular etiology. Of particular interest are the monogenic rare bone mass disorders, with the underlying genetic defect contributing to either low or high bone mass phenotype. Extensive, deep phenotyping coupled with high-throughput, cost-effective genotyping is crucial in the characterization and diagnosis of affected individuals. Massive parallel sequencing efforts have been instrumental in the discovery of novel causal genes that merit functional validation using in vitro and ex vivo cell-based techniques, and in vivo models, mainly mice and zebrafish. These translational models also serve as an excellent platform for therapeutic discovery, bridging the gap between basic science research and the clinic. Altogether, genetic studies of monogenic rare bone mass disorders have broadened our knowledge on molecular signaling pathways coordinating bone development and metabolism, disease inheritance patterns, development of new and improved bone biomarkers, and identification of novel drug targets. In this comprehensive review we describe approaches to further enhance the innovative processes taking discoveries from clinic to bench, and then back to clinic in rare bone mass disorders. We highlight the importance of cross laboratory collaboration to perform functional validation in multiple model systems after identification of a novel disease gene. We describe the monogenic forms of rare low and high rare bone mass disorders known to date, provide a roadmap to unravel the genetic determinants of monogenic rare bone mass disorders using proper phenotyping and genotyping methods, and describe different genetic validation approaches paving the way for future treatments.
  • Iso-Touru, Terhi; Wurmser, Christine; Venhoranta, Heli; Hiltpold, Maya; Savolainen, Tujia; Sironen, Anu; Fischer, Konrad; Flisikowski, Krzysztof; Fries, Ruedi; Vicente-Carrillo, Alejandro; Alvarez-Rodriguez, Manuel; Nagy, Szabolcs; Mutikainen, Mervi; Peippo, Jaana; Taponen, Juhani; Sahana, Goutam; Guldbrandtsen, Bernt; Simonen, Henri; Rodriguez-Martinez, Heriberto; Andersson, Magnus; Pausch, Hubert (2019)
    Background: Cattle populations are highly amenable to the genetic mapping of male reproductive traits because longitudinal data on ejaculate quality and dense microarray-derived genotypes are available for thousands of artificial insemination bulls. Two young Nordic Red bulls delivered sperm with low progressive motility (i.e., asthenospermia) during a semen collection period of more than four months. The bulls were related through a common ancestor on both their paternal and maternal ancestry. Thus, a recessive mode of inheritance of asthenospermia was suspected. Results: Both bulls were genotyped at 54,001 SNPs using the Illumina BovineSNP50 Bead chip. A scan for autozygosity revealed that they were identical by descent for a 2.98Mb segment located on bovine chromosome 25. This haplotype was not found in the homozygous state in 8557 fertile bulls although five homozygous haplotype carriers were expected (P=0.018). Whole genome-sequencing uncovered that both asthenospermic bulls were homozygous for a mutation that disrupts a canonical 5 splice donor site of CCDC189 encoding the coiled-coil domain containing protein 189. Transcription analysis showed that the derived allele activates a cryptic splice site resulting in a frameshift and premature termination of translation. The mutated CCDC189 protein is truncated by more than 40%, thus lacking the flagellar C1a complex subunit C1a-32 that is supposed to modulate the physiological movement of the sperm flagella. The mutant allele occurs at a frequency of 2.5% in Nordic Red cattle. Conclusions; Our study in cattle uncovered that CCDC189 is required for physiological movement of sperm flagella thus enabling active progression of spermatozoa and fertilization. A direct gene test may be implemented to monitor the asthenospermia-associated allele and prevent the birth of homozygous bulls that are infertile. Our results have been integrated in the Online Mendelian Inheritance in Animals (OMIA) database (https://omia.org/OMIA002167/9913/).
  • Lindfors, S; Polianskyte-Prause, Z; Bouslama, R; Lehtonen, E; Mannerla, M; Nisen, H; Tienari, J; Salmenkari, H; Forsgard, R; Mirtti, T; Lehto, M; Groop, PH; Lehtonen, S (2021)
    Aims/hypothesis Chronic low-grade inflammation with local upregulation of proinflammatory molecules plays a role in the progression of obesity-related renal injury. Reduced serum concentration of anti-inflammatory adiponectin may promote chronic inflammation. Here, we investigated the potential anti-inflammatory and renoprotective effects and mechanisms of action of AdipoRon, an adiponectin receptor agonist. Methods Wild-type DBA/2J mice were fed with high-fat diet (HFD) supplemented or not with AdipoRon to model obesity-induced metabolic endotoxaemia and chronic low-grade inflammation and we assessed changes in the glomerular morphology and expression of proinflammatory markers. We also treated human glomeruli ex vivo and human podocytes in vitro with AdipoRon and bacterial lipopolysaccharide (LPS), an endotoxin upregulated in obesity and diabetes, and analysed the secretion of inflammatory cytokines, activation of inflammatory signal transduction pathways, apoptosis and migration. Results In HFD-fed mice, AdipoRon attenuated renal inflammation, as demonstrated by reduced expression of glomerular activated NF-kappa B p65 subunit (NF-kappa B-p65) (70%, p < 0.001), TNF alpha (48%, p < 0.01), IL-1 beta (51%, p < 0.001) and TGF beta (46%, p < 0.001), renal IL-6 and IL-4 (21% and 20%, p < 0.05), and lowered glomerular F4/80-positive macrophage infiltration (31%, p < 0.001). In addition, AdipoRon ameliorated HFD-induced glomerular hypertrophy (12%, p < 0.001), fibronectin accumulation (50%, p < 0.01) and podocyte loss (12%, p < 0.001), and reduced podocyte foot process effacement (15%, p < 0.001) and thickening of the glomerular basement membrane (18%, p < 0.001). In cultured podocytes, AdipoRon attenuated the LPS-induced activation of the central inflammatory signalling pathways NF-kappa B-p65, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38-MAPK) (30%, 36% and 22%, respectively, p < 0.001), reduced the secretion of TNF alpha (32%, p < 0.01), and protected against podocyte apoptosis and migration. In human glomeruli ex vivo, AdipoRon reduced the LPS-induced secretion of inflammatory cytokines IL-1 beta, IL-18, IL-6 and IL-10. Conclusions/interpretation AdipoRon attenuated the renal expression of proinflammatory cytokines in HFD-fed mice and LPS-stimulated human glomeruli, which apparently contributed to the amelioration of glomerular inflammation and injury. Mechanistically, based on assays on cultured podocytes, AdipoRon reduced LPS-induced activation of the NF-kappa B-p65, JNK and p38-MAPK pathways, thereby impelling the decrease in apoptosis, migration and secretion of TNF alpha. We conclude that the activation of the adiponectin receptor by AdipoRon is a potent strategy to attenuate endotoxaemia-associated renal inflammation.
  • Dimitri, Paul; Fernandez-Luque, Luis; Banerjee, Indraneel; Bergada, Ignacio; Calliari, Luis Eduardo; Dahlgren, Jovanna; de Arriba, Antonio; Lapatto, Risto; Reinehr, Thomas; Senniappan, Senthil; Thomas-Teinturier, Cecile; Tsai, Meng-Che; Zaini, Azriyanti Anuar; Bagha, Merat; Koledova, Ekaterina (2021)
    Background: The use of technology to support health and health care has grown rapidly in the last decade across all ages and medical specialties. Newly developed eHealth tools are being implemented in long-term management of growth failure in children, a low prevalence pediatric endocrine disorder. Objective: Our objective was to create a framework that can guide future implementation and research on the use of eHealth tools to support patients with growth disorders who require growth hormone therapy. Methods: A total of 12 pediatric endocrinologists with experience in eHealth, from a wide geographical distribution, participated in a series of online discussions. We summarized the discussions of 3 workshops, conducted during 2020, on the use of eHealth in the management of growth disorders, which were structured to provide insights on existing challenges, opportunities, and solutions for the implementation of eHealth tools across the patient journey, from referral to the end of pediatric therapy. Results: A total of 815 responses were collected from 2 questionnaire-based activities covering referral and diagnosis of growth disorders, and subsequent growth hormone therapy stages of the patient pathway, relating to physicians, nurses, and patients, parents, or caregivers. We mapped the feedback from those discussions into a framework that we developed as a guide to integration of eHealth tools across the patient journey. Responses focused on improved clinical management, such as growth monitoring and automation of referral for early detection of growth disorders, which could trigger rapid evaluation and diagnosis. Patient support included the use of eHealth for enhanced patient and caregiver communication, better access to educational opportunities, and enhanced medical and psychological support during growth hormone therapy management. Given the potential availability of patient data from connected devices, artificial intelligence can be used to predict adherence and personalize patient support. Providing evidence to demonstrate the value and utility of eHealth tools will ensure that these tools are widely accepted, trusted, and used in clinical practice, but implementation issues (eg, adaptation to specific clinical settings) must be addressed. Conclusions: The use of eHealth in growth hormone therapy has major potential to improve the management of growth disorders along the patient journey. Combining objective clinical information and patient adherence data is vital in supporting decision-making and the development of new eHealth tools. Involvement of clinicians and patients in the process of integrating such technologies into clinical practice is essential for implementation and developing evidence that eHealth tools can provide value across the patient pathway.
  • Trojnar, Eszter; Jozsi, Mihaly; Uray, Katalin; Csuka, Dorottya; Szilagyi, Agnes; Milosevic, Danko; Stojanovic, Vesna D.; Spasojevic, Brankica; Rusai, Krisztina; Mueller, Thomas; Arbeiter, Klaus; Kelen, Kata; Szabo, Attila J.; Reusz, Gyorgy S.; Hyvarinen, Satu; Jokiranta, T. Sakari; Prohaszka, Zoltan (2017)
    Introduction: In autoimmune atypical hemolytic uremic syndrome (aHUS), the complement regulator factor H (FH) is blocked by FH autoantibodies, while 90% of the patients carry a homozygous deletion of its homolog complement FH-related protein 1 (CFHR1). The functional consequence of FH-blockade is widely established; however, the molecular basis of autoantibody binding and the role of CFHR1 deficiency in disease pathogenesis are still unknown. We performed epitope mapping of FH to provide structural insight in the autoantibody recruitment on FH and potentially CFHR1. Methods: Eight anti-FH positive aHUS patients were enrolled in this study. With overlapping synthetic FH and CFHR1 peptides, we located the amino acids (aa) involved in binding of acute and convalescence stage autoantibodies. We confirmed the location of the mapped epitopes using recombinant FH domains 19-20 that carried single-aa substitutions at the suspected antibody binding sites in three of our patients. Location of the linear epitopes and the introduced point mutations was visualized using crystal structures of the corresponding domains of FH and CFHR1. Results: We identified three linear epitopes on FH (aa1157-1171; aa1177-1191; and aa1207-1226) and one on CFHR1 (aa276-290) that are recognized both in the acute and convalescence stages of aHUS. We observed a similar extent of autoantibody binding to the aHUS-specific epitope aa1177-1191 on FH and aa276-290 on CFHR1, despite seven of our patients being deficient for CFHR1. Epitope mapping with the domain constructs validated the location of the linear epitopes on FH with a distinct autoantibody binding motif within aa1183-1198 in line with published observations. Summary: According to the results, the linear epitopes we identified are located close to each other on the crystal structure of FH domains 19-20. This tertiary configuration contains the amino acids reported to be involved in C3b and sialic acid binding on the regulator, which may explain the functional deficiency of FH in the presence of auto antibodies. The data we provide identify the exact structures involved in autoantibody recruitment on FH and confirm the presence of an autoantibody binding epitope on CFHR1.
  • Seppala, Jussi; Koponen, Hannu; Kautiainen, Hannu; Eriksson, Johan G.; Kampman, Olli; Leiviska, Jaana; Mannisto, Satu; Mantyselka, Pekka; Oksa, Heikki; Ovaskainen, Yrj; Viikki, Merja; Vanhala, Mauno; Seppala, Jussi (2013)
  • Korkalo, Liisa; Erkkola, Maijaliisa; Heinonen, Arja E.; Freese, Riitta; Selvester, Kerry; Mutanen, Marja (2017)
    Purpose In low-income settings, dietary diversity scores (DDSs) often predict the micronutrient adequacy of diets, but little is known about whether they predict levels of biochemical indicators of micronutrient status. Methods In 2010, we studied two samples of non-pregnant 14-to 19-year-old girls in central Mozambique, the first in January-February ('hunger season'; n = 227) and the second in May-June (harvest season; n = 223). In this paper, we examined whether a low Women's Dietary Diversity Score (WDDS) predicts a low concentration of haemoglobin, serum ferritin, zinc, and folate, and plasma retinol in adolescent Mozambican girls. We constructed three scores: WDDS based on 24-h recalls, WDDS15g based on 24-h recall and employing a 15 g limit, and 7dWDDS based on 7-day food frequency questionnaires. Logistic regression models, stratified by season, were used to estimate the odds of having a low concentration of a status indicator ( Results In January-February, after adjusting for confounders, a low ( Conclusions Our data from Mozambique suggest that dietary diversity is associated with serum zinc, but this association seems to be limited to the hunger season.
  • German HNPCC Consortium; Dutch Lynch Syndrome Collaborative; Finnish Lynch Syndrome Registry; Engel, Christoph; Ahadova, Aysel; Seppälä, Toni T.; Lepistö, Anna; Renkonen-Sinisalo, Laura; Vasen, Hans F. (2020)
    BACKGROUND & AIMS: Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via different pathways. We studied associations between Lynch syndrome-associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients. METHODS: We combined clinical and molecular data from 3 studies. We obtained clinical data from 2747 patients with Lynch syndrome associated with variants in MLH1, MSH2, or MSH6 from Germany, the Netherlands, and Finland who received at least 2 surveillance colonoscopies and were followed for a median time of 7.8 years for development of adenomas or CRC. We performed DNA sequence analyses of 48 colorectal tumors (from 16 patients with mutations in MLH1, 29 patients with mutations in MSH2, and 3 with mutations in MSH6) for somatic mutations in APC and CTNNB1. RESULTS: Risk of advanced adenoma in 10 years was 17.8% in patients with pathogenic variants in MSH2 vs 7.7% in MLH1 (P <.001). Higher proportions of patients with pathogenic variants in MLH1 or MSH2 developed CRC in 10 years (11.3% and 11.4%) than patients with pathogenic variants in MSH6 (4.7%) (P = .001 and P = .003 for MLH1 and MSH2 vs MSH6, respectively). Somatic mutations in APC were found in 75% of tumors from patients with pathogenic variants in MSH2 vs 11% in MLH1 (P = .015). Somatic mutations in CTNNB1 were found in 50% of tumors from patients with pathogenic variants in MLH1 vs 7% in MSH2 (P = .002). None of the 3 tumors with pathogenic variants in MSH6 had a mutation in CTNNB1, but all had mutations in APC. CONCLUSIONS: In an analysis of clinical and DNA sequence data from patients with Lynch syndrome from 3 countries, we associated pathogenic variants in MMR genes with risk of adenoma and CRC, and somatic mutations in APC and CTNNB1 in colorectal tumors. If these findings are confirmed, surveillance guidelines might be adjusted based on MMR gene variants.
  • Malkamäki, Aapo Erkki Matias; Sharma, Vivek (2019)
    Mitochondrial cytochrome c oxidase couples the reduction of oxygen to proton pumping. Despite an overall good understanding of its molecular mechanism, the role of cardiolipin in protein function is not understood. Here, we have studied the cardiolipin-protein interactions in a dynamic context by means of atomistic molecular dynamics simulations performed on the entire structure of monomeric and dimeric forms of the enzyme. Several microseconds of simulation data reveal that the crystallographic cardiolipin molecules that glue two monomers together bind weakly in hybrid and single-component lipid bilayers and dissociate rapidly. Atomistic simulations performed in the absence of tightly bound cardiolipin molecules strongly perturb the structural integrity of subunits III and Vila, thereby highlighting an indispensable nature of lipid-protein interactions in enzyme function such as proton uptake and oxygen channeling. Our results demonstrate the strength of molecular simulations in providing direct atomic description of lipid-protein processes that are difficult to achieve experimentally.
  • Kausar, Mehran; Ul Ain, Noor; Hayat, Farzana; Fatima, Hunain; Azim, Saad; Ullah, Hazrat; Mushtaq, Murva; Khalid, Sumbal; Hussain, Shahid; Naz, Sadaf; Janjua, Jamal; Bin Amjad, Saad; Baig, Ruqia Mehmood; Makitie, Outi; Qamar, Raheel; Ikegawa, Shiro; Gen, Nishimura; Khor, Chiea Chuen; Foo, Jia Nee; Siddiqi, Saima (2022)
    Background Skeletal dysplasia is a heterogeneous group of disorders. Spondyloepiphyseal dysplasias comprise one subgroup. Deficiency of carbohydrate sulfotransferase 3 has been reported in a small number of patients with recessively inherited spondyloepiphyseal dysplasia with joint dislocation, short stature and scoliosis. We report here molecular and clinical findings of affected individuals in three consanguineous Pakistani families. Affected individuals in all three families had a uniform phenotype including severe short stature, multiple dislocated joints, progressive scoliosis and facial dysmorphism. Methods Clinical evaluation was done for three unrelated families. Radiological survey of bones was completed for patients from two of the families. Whole exome sequencing index patients from each family was performed followed by Sanger sequencing for validation of segregation of identified variants in respective families. In-silico analysis for determining pathogenicity of identified variants and conservation was done. Results Whole-exome sequencing revealed biallelic variants c.590 T > C;p.(Leu197Pro), c.603C > A;p.(Tyr201Ter) and c.661C > T;p.(Arg221Cys) in CHST3 (NM_004273.5) in the three families with eight, five and two affected individuals, respectively. Contrary to previous reports, affected individuals in none of the families exhibited a hearing loss. Conclusion We describe genotypic and phenotypic findings of three unrelated families with spondyloepiphyseal dysplasia. Our study confirms phenotypic variability and adds to the genotypic spectrum of spondyloepiphyseal dysplasia.
  • Chen, Tingting; Hedman, Lea; Mattila, Petri S.; Jartti, Laura; Jartti, Tuomas; Ruuskanen, Olli; Söderlund-Venermo, Maria; Hedman, Klaus (2012)
  • Szibor, Marten; Dhandapani, Praveen K.; Dufour, Eric; Holmstrom, Kira M.; Zhuang, Yuan; Salwig, Isabelle; Wittig, Ilka; Heidler, Juliana; Gizatullina, Zemfira; Gainutdinov, Timur; Fuchs, Helmut; Gailus-Durner, Valerie; de Angelis, Martin Hrabe; Nandania, Jatin; Velagapudi, Vidya; Wietelmann, Astrid; Rustin, Pierre; Gellerich, Frank N.; Jacobs, Howard T.; Braun, Thomas; German Mouse Clinic Consortium (2017)
    Plants and many lower organisms, but not mammals, express alternative oxidases (AOXs) that branch the mitochondrial respiratory chain, transferring electrons directly from ubiquinol to oxygen without proton pumping. Thus, they maintain electron flow under conditions when the classical respiratory chain is impaired, limiting excess production of oxygen radicals and supporting redox and metabolic homeostasis. AOX from Ciona intestinalis has been used to study and mitigate mitochondrial impairments in mammalian cell lines, Drosophila disease models and, most recently, in the mouse, where multiple lentivector-AOX transgenes conferred substantial expression in specific tissues. Here, we describe a genetically tractable mouse model in which Ciona AOX has been targeted to the Rosa26 locus for ubiquitous expression. The AOX(Rosa26) mouse exhibited only subtle phenotypic effects on respiratory complex formation, oxygen consumption or the global metabolome, and showed an essentially normal physiology. AOX conferred robust resistance to inhibitors of the respiratory chain in organello; moreover, animals exposed to a systemically applied LD50 dose of cyanide did not succumb. The AOX(Rosa26) mouse is a useful tool to investigate respiratory control mechanisms and to decipher mitochondrial disease aetiology in vivo.
  • Hanninen, Reetta L.; Ahonen, Saija; Marquez, Merce; Myohanen, Maarit J.; Hytonen, Marjo K.; Lohi, Hannes (2015)
    Mitochondrial DNA depletion syndromes (MDS) are often serious autosomal recessively inherited disorders characterized by tissue-specific mtDNA copy number reduction. Many genes, including MPV17, are associated with the hepatocerebral form of MDS. MPV17 encodes for a mitochondrial inner membrane protein with a poorly characterized function. Several MPV17 mutations have been reported in association with a heterogeneous group of early-onset manifestations, including liver disease and neurological problems. Mpv17-deficient mice present renal and hearing defects. We describe here a MPV17 truncation mutation in dogs. We found a 1-bp insertion in exon 4 of the MPV17 gene, resulting in a frameshift and early truncation of the encoded protein. The mutation halves MPV17 expression in the lymphocytes of the homozygous dogs and the truncated protein is not translated in transfected cells. The insertion mutation is recurrent and exists in many unrelated breeds, although is highly enriched in the Boxer breed. Unexpectedly, despite the truncation of MPV17, we could not find any common phenotypes in the genetically affected dogs. The lack of observable phenotype could be due to a late onset, mild symptoms or potential tissue-specific compensatory mechanisms. This study suggests species-specific differences in the manifestation of the MPV17 defects and establishes a novel large animal model to further study MPV17 function and role in mitochondrial biology.
  • Munteanu, Iulia; Kalimo, Hannu; Saraste, Antti; Nishino, Ichizo; Minassian, Berge A. (2017)
    X-linked myopathy with excessive autophagy (XMEA), caused by mutations of the VMA21 gene, is a strictly skeletal muscle disease. Extensive studies in yeast established VMA21 as the master assembly chaperone of V-ATPase, the complex multisubunit proton pump that acidifies organelles and that is vital to all mammalian tissues. As such, skeletal muscle disease exclusivity in XMEA is highly surprising. We now show that the severest VMA21 mutation, c.164-6t>g, does result in XMEA-typical pathology with autophagic vacuolar changes outside skeletal muscle, namely in the heart. However, even patients with this mutation do not exhibit clinical extramuscular disease, including cardiac disease, despite extreme skeletal muscle wasting to the extent of ventilation dependence. Uncovering the unique skeletal muscle vulnerability to defective organellar acidification, and resultant tissue-destructive excessive autophagy, will be informative to the understanding of muscle physiology. Alternatively, understanding extramuscular resistance to VMA21 mutation might disclose heretofore unknown mammalian V-ATPase assembly chaperones other than VMA21. (C) 2016 Elsevier B.V. All rights reserved.
  • Vuorinen, Pekka J.; Rokka, Mervi; Ritvanen, Tiina; Käkelä, Reijo; Nikonen, Soili; Pakarinen, Tapani; Keinänen, Marja (2020)
    Salmonines in the Baltic Sea and North American lakes suffer from thiamine (vitamin B1) deficiency, which is connected to an abundant lipid-rich diet containing substantial amounts of polyunsaturated fatty acids (PUFAs). In the Baltic region, this is known as the M74 syndrome. It affects both adult salmon (Salmo salar) and especially their offspring, impairing recruitment. However, very little is known about the thiamine and lipid metabolism of salmon during feeding and spawning migrations in the Baltic Sea. In this study, salmon females were sampled along the spawning run from the southern Baltic Proper in four locations at sea and finally at spawning in a river at the Bothnian Bay in a year with insignificant M74 mortality. Changes in concentrations of thiamine and its components in muscle, ovaries, and the liver and other biochemical indices potentially relating to lipid and fatty acid metabolism were investigated. The results provide further evidence of the role of peroxidation of PUFAs in eliciting thiamine deficiency in salmon: During the entire spawning run, the muscle total lipid content decreased by 50%, palmitic acid (16:0) by 62%, and docosahexaenoic acid (DHA, 22:6n-3) by 45%. The concentration of total thiamine decreased significantly until the spawning in the liver and ovaries, 66 and 70% respectively. In the muscle, the proportion of thiamine pyrophosphate of total thiamine increased with the use of muscular lipid stores. There was no trend in the concentration of total carotenoids during the spawning run. The doubling of the concentration of hepatic malondialdehyde indicated peroxidation of PUFAs, and the mobilisation of body lipids suppressed the activity of glucose-6-phosphate dehydrogenase, as consumed dietary lipids would also have done.