PUBLICATION
NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease
- Authors
- Uusimaa, J., Kaarteenaho, R., Paakkola, T., Tuominen, H., Karjalainen, M.K., Nadaf, J., Varilo, T., Uusi-Mäkelä, M., Suo-Palosaari, M., Pietilä, I., Hiltunen, A.E., Ruddock, L., Alanen, H., Biterova, E., Miinalainen, I., Salminen, A., Soininen, R., Manninen, A., Sormunen, R., Kaakinen, M., Vuolteenaho, R., Herva, R., Vieira, P., Dunder, T., Kokkonen, H., Moilanen, J.S., Rantala, H., Nogee, L.M., Majewski, J., Rämet, M., Hallman, M., Hinttala, R.
- ID
- ZDB-PUB-180210-6
- Date
- 2018
- Source
- Acta Neuropathologica 135(5): 727-742 (Journal)
- Registered Authors
- Keywords
- Brain angiogenesis, Central nervous system, Cerebropulmonary disease, Interstitial fibrosis, Multi-organ disease, Neurodegeneration
- MeSH Terms
-
- Angiomatosis/genetics*
- Angiomatosis/pathology
- Angiomatosis/physiopathology
- Animals
- Animals, Genetically Modified
- Brain/metabolism
- Brain/pathology
- Brain Diseases/genetics*
- Brain Diseases/pathology
- Brain Diseases/physiopathology
- Cells, Cultured
- Family
- Fatal Outcome
- Genetic Variation*
- Humans
- Infant
- Intracellular Signaling Peptides and Proteins/genetics*
- Intracellular Signaling Peptides and Proteins/metabolism
- Liver Diseases/genetics
- Liver Diseases/pathology
- Liver Diseases/physiopathology
- Male
- Mice, Inbred C57BL
- Neurodegenerative Diseases/genetics*
- Neurodegenerative Diseases/pathology
- Neurodegenerative Diseases/physiopathology
- Prospective Studies
- Pulmonary Fibrosis/genetics*
- Pulmonary Fibrosis/pathology
- Pulmonary Fibrosis/physiopathology
- Syndrome
- Zebrafish
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 29423877 Full text @ Acta Neuropathol.
Citation
Uusimaa, J., Kaarteenaho, R., Paakkola, T., Tuominen, H., Karjalainen, M.K., Nadaf, J., Varilo, T., Uusi-Mäkelä, M., Suo-Palosaari, M., Pietilä, I., Hiltunen, A.E., Ruddock, L., Alanen, H., Biterova, E., Miinalainen, I., Salminen, A., Soininen, R., Manninen, A., Sormunen, R., Kaakinen, M., Vuolteenaho, R., Herva, R., Vieira, P., Dunder, T., Kokkonen, H., Moilanen, J.S., Rantala, H., Nogee, L.M., Majewski, J., Rämet, M., Hallman, M., Hinttala, R. (2018) NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease. Acta Neuropathologica. 135(5):727-742.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping