Browsing by Subject "MEMBRANE-PROTEIN"

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  • Lepelley, Alice; Della Mina, Erika; Van Nieuwenhove, Erika; Waumans, Lise; Fraitag, Sylvie; Rice, Gillian I.; Dhir, Ashish; Fremond, Marie-Louise; Rodero, Mathieu P.; Seabra, Luis; Carter, Edwin; Bodemer, Christine; Buhas, Daniela; Callewaert, Bert; de Lonlay, Pascale; De Somer, Lien; Dyment, David A.; Faes, Fran; Grove, Lucy; Holden, Simon; Hully, Marie; Kurian, Manju A.; McMillan, Hugh J.; Suetens, Kristin; Tyynismaa, Henna; Chhun, Stephanie; Wai, Timothy; Wouters, Carine; Bader-Meunier, Brigitte; Crow, Yanick J. (2021)
    Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated gene (ISG) expression in blood. We determined each to harbor a previously described de novo dominant-negative heterozygous mutation in ATAD3A, encoding ATPase family AAA domain-containing protein 3A (ATAD3A). We identified five further patients with mutations in ATAD3A and recorded up regulated ISG expression and interferon alpha protein in four of them. Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signaling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signaling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA. Thus, mutations in the mitochondrial membrane protein ATAD3A define a novel type I interferonopathy.
  • Ruskamo, Salla; Nieminen, Tuomo; Kristiansen, Cecilie K.; Vatne, Guro H.; Baumann, Anne; Hallin, Erik I.; Raasakka, Arne; Joensuu, Paivi; Bergmann, Ulrich; Vattulainen, Ilpo; Kursula, Petri (2017)
    Charcot-Marie-Tooth (CMT) disease is one of the most common inherited neuropathies. Recently, three CMT1-associated point mutations (I43N, T51P, and I52T) were discovered in the abundant peripheral myelin protein P2. These mutations trigger abnormal myelin structure, leading to reduced nerve conduction velocity, muscle weakness, and distal limb atrophy. P2 is a myelin-specific protein expressed by Schwann cells that binds to fatty acids and membranes, contributing to peripheral myelin lipid homeostasis. We studied the molecular basis of the P2 patient mutations. None of the CMT1-associated mutations alter the overall folding of P2 in the crystal state. P2 disease variants show increased aggregation tendency and remarkably reduced stability, T51P being most severe. In addition, P2 disease mutations affect protein dynamics. Both fatty acid binding by P2 and the kinetics of its membrane interactions are affected by the mutations. Experiments and simulations suggest opening of the beta barrel in T51P, possibly representing a general mechanism in fatty acid-binding proteins. Our findings demonstrate that altered biophysical properties and functional dynamics of P2 may cause myelin defects in CMT1 patients. At the molecular level, a few malformed hydrogen bonds lead to structural instability and misregulation of conformational changes related to ligand exchange and membrane binding.
  • Vanaveski, Taavi; Singh, Katyayani; Narvik, Jane; Eskla, Kattri-Liis; Visnapuu, Tanel; Heinla, Indrek; Jayaram, Mohan; Innos, Jurgen; Lillevali, Kersti; Philips, Mari-Anne; Vasar, Eero (2017)
    IgLON family is composed of five genes: Lsamp, Ntm, Opcml, Negr1, and Iglon5; encoding for five highly homologous neural adhesion proteins that regulate neurite outgrowth and synapse formation. In the current study we performed in silico analysis revealing that Ntm and Opcml display similar genomic structure as previously reported for Lsamp, characterized by two alternative promotors 1a and 1b. Negr1 and Iglon5 transcripts have uniform 5' region, suggesting single promoter. Iglon5, the recently characterized family member, shares high level of conservation and structural qualities characteristic to IgLON family such as N-terminal signal peptide, three Ig domains, and GPI anchor binding site. By using custom 5'-isoform-specific TaqMan gene-expression assay, we demonstrated heterogeneous expression of IgLON transcripts in different areas of mouse brain and several-fold lower expression in selected tissues outside central nervous system. As an example, the expression of IgLON transcripts in urogenital and reproductive system is in line with repeated reports of urogenital tumors accompanied by mutations in IgLON genes. Considering the high levels of intra-family homology shared by IgLONs, we investigated potential compensatory effects at the level of IgLON isoforms in the brains of mice deficient of one or two family members. We found that the lack of IgLONs is not compensated by a systematic quantitative increase of the other family members. On the contrary, the expression of Ntm 1a transcript and NEGR1 protein was significantly reduced in the frontal cortex of Lsamp-deficient mice suggesting that the expression patterns within IgLON family are balanced coherently. The actions of individual IgLONs, however, can be antagonistic as demonstrated by differential expression of Syp in deletion mutants of IgLONs. In conclusion, we show that the genomic twin-promoter structure has impact on both anatomical distribution and intra-family interactions of IgLON family members. Remarkable variety in the activity levels of 1a and 1b promoters both in the brain and in other tissues, suggests complex functional regulation of IgLONs by alternative signal peptides driven by 1a and 1b promoters.
  • Dillard, Kati J.; Ochs, Matthias; Niskanen, Julia E.; Arumilli, Meharji; Donner, Jonas; Kyöstilä, Kaisa; Hytönen, Marjo K.; Anttila, Marjukka; Lohi, Hannes (2020)
    Neonatal interstitial lung diseases due to abnormal surfactant biogenesis are rare in humans and have never been reported as a spontaneous disorder in animals. We describe here a novel lung disorder in Airedale Terrier (AT) dogs with clinical symptoms and pathology similar to the most severe neonatal forms of human surfactant deficiency. Lethal hypoxic respiratory distress and failure occurred within the first days or weeks of life in the affected puppies. Transmission electron microscopy of the affected lungs revealed maturation arrest in the formation of lamellar bodies (LBs) in the alveolar epithelial type II (AECII) cells. The secretory organelles were small and contained fewer lamellae, often in combination with small vesicles surrounded by an occasionally disrupted common limiting membrane. A combined approach of genome-wide association study and whole exome sequencing identified a recessive variant, c.1159G>A, p.(E387K), in LAMP3, a limiting membrane protein of the cytoplasmic surfactant organelles in AECII cells. The substitution resides in the LAMP domain adjacent to a conserved disulfide bond. In summary, this study describes a novel interstitial lung disease in dogs, identifies a new candidate gene for human surfactant dysfunction and brings important insights into the essential role of LAMP3 in the process of the LB formation. Author summary We have characterized a lethal lung disease in neonatal Airedale Terrier dogs. The pathological features of the disease resemble those of the surfactant dysfunction in newborn babies. Surfactant is essential for lung function and we observed a maturation defect in the surfactant producing organelles of the lung epithelial type II cells. Genetic analyses revealed a recessive variant in the lysosome associated membrane LAMP3 gene. LAMP3 is a structural, limiting membrane protein of the surfactant organelles. This study provides an excellent candidate gene for human surfactant disorders as well as new insights into LAMP3 biology and pathophysiology while the affected breed will benefit from genetic testing to eradicate this severe disease.
  • Rönnberg, Tuomas; Jääskeläinen, Kirsi Maria; Blot, Guillaume; Parviainen, Ville; Vaheri, Antti; Renkonen, Risto; Bouloy, Michele; Plyusnin, Alexander (2012)
  • Korkama, Eva-Stina; Armstrong, Anna-Elina; Jarva, Hanna; Meri, Seppo (2018)
    Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired syndrome characterized by intravascular hemolysis, thrombosis, and bone marrow failure. The disease is caused by a mutation in the PIG-A gene that leads to the lack of glycosylphosphatidylinositol-anchored complement regulatory molecules CD55 and CD59 on affected blood cell surfaces. In previous studies, spontaneous clinical remissions have been described. The disease manifestations are very heterogeneous, and we wanted to examine if true remissions and disappearance of the clone occur. In a follow-up of a nation-wide cohort of 106 Finnish patients with a PNH clone, we found six cases, where the clone disappeared or was clearly diminished. Two of the patients subsequently developed leukemia, while the other four are healthy and in clinical remission. According to our data, spontaneous remissions are not as frequent as described earlier. Since the disappearance of the PNH cell clone may indicate either a favorable or a poor outcome-remission or malignancy-careful clinical monitoring in PNH is mandatory. Nevertheless, true remissions occur, and further studies are needed to understand the immunological background of this phenomenon and to obtain a better understanding of the natural history of the disease.