NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA) : characterisation of a novel cerebropulmonary disease
| Autor: | Lawrence M. Nogee, Ilkka Pietilä, Raija Soininen, Päivi Vieira, Teppo Varilo, Raija Sormunen, Ekaterina Biterova, Maria Suo-Palosaari, Mika Rämet, Minna K. Karjalainen, Teija Paakkola, Riitta Herva, Annamari Salminen, Jukka S. Moilanen, Anniina E. Hiltunen, Hannu Tuominen, Meri I. E. Uusi-Mäkelä, Jacek Majewski, Aki Manninen, Riitta Kaarteenaho, Mikko Hallman, Johanna Uusimaa, Mika Kaakinen, Heikki Rantala, Reetta Vuolteenaho, Heli I. Alanen, Javad Nadaf, Lloyd W. Ruddock, Teija Dunder, Ilkka Miinalainen, Reetta Hinttala, Hannaleena Kokkonen |
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| Přispěvatelé: | Medicum, Department of Medical and Clinical Genetics |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Pathology Pulmonary Fibrosis Animals Genetically Modified Fatal Outcome Fibrosis Prospective Studies Cells Cultured Zebrafish Brain Diseases Interstitial fibrosis Liver Diseases Neurodegeneration Intracellular Signaling Peptides and Proteins Brain Neurodegenerative Diseases Multi-organ disease Syndrome Angiomatosis 3. Good health medicine.anatomical_structure medicine.symptom NKX2-1 Brain angiogenesis medicine.medical_specialty DATABASE Neuropathology Asymptomatic Pathology and Forensic Medicine Frameshift mutation White matter 03 medical and health sciences Cellular and Molecular Neuroscience Benign hereditary chorea medicine Animals Humans Family business.industry MUTATIONS 3112 Neurosciences Genetic Variation Infant Zebrafish Proteins medicine.disease Cerebropulmonary disease BENIGN HEREDITARY CHOREA Mice Inbred C57BL 030104 developmental biology Central nervous system Neurology (clinical) 3111 Biomedicine business |
| Popis: | A novel multi-organ disease that is fatal in early childhood was identified in three patients from two non-consanguineous families. These children were born asymptomatic but at the age of 2 months they manifested progressive multi-organ symptoms resembling no previously known disease. The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. In the affected children, neuropathology revealed increased angiomatosis-like leptomeningeal, cortical and superficial white matter vascularisation and congestion, vacuolar degeneration and myelin loss in white matter, as well as neuronal degeneration. Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver. A whole-exome sequencing of the two unrelated families with the affected children revealed the transmission of two heterozygous variants in the NHL repeat-containing protein 2 (NHLRC2); an amino acid substitution p.Asp148Tyr and a frameshift 2-bp deletion p.Arg201GlyfsTer6. NHLRC2 is highly conserved and expressed in multiple organs and its function is unknown. It contains a thioredoxin-like domain; however, an insulin turbidity assay on human recombinant NHLRC2 showed no thioredoxin activity. In patient-derived fibroblasts, NHLRC2 levels were low, and only p.Asp148Tyr was expressed. Therefore, the allele with the frameshift deletion is likely non-functional. Development of the Nhlrc2 null mouse strain stalled before the morula stage. Morpholino knockdown of nhlrc2 in zebrafish embryos affected the integrity of cells in the midbrain region. This is the first description of a fatal, early-onset disease; we have named it FINCA disease based on the combination of pathological features that include fibrosis, neurodegeneration, and cerebral angiomatosis. |
| Databáze: | OpenAIRE |
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