University of Oulu

Hiltunen, A.E., Kangas, S.M., Ohlmeier, S. et al. Variant in NHLRC2 leads to increased hnRNP C2 in developing neurons and the hippocampus of a mouse model of FINCA disease. Mol Med 26, 123 (2020).

Variant in NHLRC2 leads to increased hnRNP C2 in developing neurons and the hippocampus of a mouse model of FINCA disease

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Author: Hiltunen, Anniina E.1,2; Kangas, Salla M.1,2; Ohlmeier, Steffen3;
Organizations: 1Medical Research Center Oulu and PEDEGO Research Unit, University of Oulu and Oulu University Hospital, PO Box 5000, 90014, Oulu, Finland
2Biocenter Oulu, University of Oulu, Oulu, Finland
3Proteomics Core Facility, Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, PO Box 5400, Oulu, 90014, Finland
4Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden
5A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland
6The Hospital for Sick Children, Toronto, Canada
7Faculty of Medicine, University of Toronto, Toronto, Canada
8Tissue Engineering Laboratory, Hepia/HES-SO, University of Applied Sciences Western Switzerland, Geneva, Switzerland
9Department of Pathology, Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland
10Department of Pathology, Oulu University Hospital, Oulu, Finland
11Research Unit of Internal Medicine, Respiratory Research, University of Oulu, Oulu, Finland
12Medical Research Center Oulu and Unit of Internal Medicine and Respiratory Medicine, Oulu University Hospital, Oulu, Finland
13Clinic for Children and Adolescents, Paediatric Neurology Unit, Oulu University Hospital, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 6.3 MB)
Persistent link:
Language: English
Published: Springer Nature, 2020
Publish Date: 2021-01-27


Background: FINCA disease is a pediatric cerebropulmonary disease caused by variants in the NHL repeat-containing 2 (NHLRC2) gene. Neurological symptoms are among the first manifestations of FINCA disease, but the consequences of NHLRC2 deficiency in the central nervous system are currently unexplored.

Methods: The orthologous mouse gene is essential for development, and its complete loss leads to early embryonic lethality. In the current study, we used CRISPR/Cas9 to generate an Nhlrc2 knockin (KI) mouse line, harboring the FINCA patient missense mutation (c.442G > T, p.Asp148Tyr). A FINCA mouse model, resembling the compound heterozygote genotype of FINCA patients, was obtained by crossing the KI and Nhlrc2 knockout mouse lines. To reveal NHLRC2-interacting proteins in developing neurons, we compared cortical neuronal precursor cells of E13.5 FINCA and wild-type mouse embryos by two-dimensional difference gel electrophoresis.

Results: Despite the significant decrease in NHLRC2, the mice did not develop severe early onset multiorgan disease in either sex. We discovered 19 altered proteins in FINCA neuronal precursor cells; several of which are involved in vesicular transport pathways and actin dynamics which have been previously reported in other cell types including human to have an association with dysfunctional NHLRC2. Interestingly, isoform C2 of hnRNP C1/C2 was significantly increased in both developing neurons and the hippocampus of adult female FINCA mice, connecting NHLRC2 dysfunction with accumulation of RNA binding protein.

Conclusions: We describe here the first NHLRC2-deficient mouse model to overcome embryonic lethality, enabling further studies on predisposing and causative mechanisms behind FINCA disease. Our novel findings suggest that disrupted RNA metabolism may contribute to the neurodegeneration observed in FINCA patients.

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Series: Molecular medicine
ISSN: 1076-1551
ISSN-E: 1528-3658
ISSN-L: 1076-1551
Volume: 26
Issue: 1
Article number: 123
DOI: 10.1186/s10020-020-00245-4
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: This work was conducted with support from the Research Council for Health of the Academy of Finland (R.H., Decision Numbers 266498, 273790, 303996 and 317711), Academy of Finland profiling programme (R.H., Decision Number 311934), the Foundation for Pediatric Research, Finland (J.U. and R.H.), Sigrid Jusélius Foundation (M.H., decision number 1024), Biocenter Oulu (J.U. and R.H.) and State Grants for Health Research, Clinic for Children and Adolescents, Oulu University Hospital, Oulu, Finland (J.U.)
Academy of Finland Grant Number: 266498
Detailed Information: 266498 (Academy of Finland Funding decision)
273790 (Academy of Finland Funding decision)
303996 (Academy of Finland Funding decision)
317711 (Academy of Finland Funding decision)
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