Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/22827
Title: Bi-allelic LoF NRROS Variants Impairing Active TGF-β1 Delivery Cause a Severe Infantile-Onset Neurodegenerative Condition with Intracranial Calcification.
Austin Authors: Dong, Xiaomin;Tan, Natalie B;Howell, Katherine B;Barresi, Sabina;Freeman, Jeremy L;Vecchio, Davide;Piccione, Maria;Radio, Francesca Clementina;Calame, Daniel;Zong, Shan;Eggers, Stefanie;Scheffer, Ingrid E ;Tan, Tiong Y;Van Bergen, Nicole J;Tartaglia, Marco;Christodoulou, John;White, Susan M
Affiliation: Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome 00146, Italy
Department of Neurology, Royal Children's Hospital, Parkville, Victoria 3052, Australia
Department of Science for Health Promotion and Mother and Child Care, Università degli Studi di Palermo, Palermo 90127, Italy
Department of Paediatrics, University of Melbourne, Parkville, Victoria 3052, Australia
Victorian Clinical Genetics Services, Parkville, Victoria 3052, Australia
Baylor College of Medicine, Houston, TX 77030, USA
Texas Children's Hospital, Houston, TX 77030, USA
Murdoch Children's Research Institute, Parkville, Victoria 3052, Australia
Issue Date: 2-Apr-2020
metadata.dc.date: 2020-03-13
Publication information: American journal of human genetics 2020; 106(4): 559-569
Abstract: Negative regulator of reactive oxygen species (NRROS) is a leucine-rich repeat-containing protein that uniquely associates with latent transforming growth factor beta-1 (TGF- β1) and anchors it on the cell surface; this anchoring is required for activation of TGF-β1 in macrophages and microglia. We report six individuals from four families with bi-allelic variants in NRROS. All affected individuals had neurodegenerative disease with refractory epilepsy, developmental regression, and reduced white matter volume with delayed myelination. The clinical course in affected individuals began with normal development or mild developmental delay, and the onset of seizures occurred within the first year of life, followed by developmental regression. Intracranial calcification was detected in three individuals. The phenotypic features in affected individuals are consistent with those observed in the Nrros knockout mouse, and they overlap with those seen in the human condition associated with TGF-β1 deficiency. The disease-causing NRROS variants involve two significant functional NRROS domains. These variants result in aberrant NRROS proteins with impaired ability to anchor latent TGF-β1 on the cell surface. Using confocal microscopy in HEK293T cells, we demonstrate that wild-type and mutant NRROS proteins co-localize with latent TGF-β1 intracellularly. However, using flow cytometry, we show that our mutant NRROS proteins fail to anchor latent TGF-β1 at the cell surface in comparison to wild-type NRROS. Moreover, wild-type NRROS rescues the defect of our disease-associated mutants in presenting latent TGF-β1 to the cell surface. Taken together, our findings suggest that loss of NRROS function causes a severe childhood-onset neurodegenerative condition with features suggestive of a disordered response to inflammation.
URI: http://ahro.austin.org.au/austinjspui/handle/1/22827
DOI: 10.1016/j.ajhg.2020.02.014
ORCID: 0000-0002-2311-2174
PubMed URL: 32197075
Type: Journal Article
Subjects: NRROS
TGF-β1
intracranial calcification
mutation
neurodegeneration
neuroinflammation
Appears in Collections:Journal articles

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