TY - JOUR
T1 - Bi-allelic LoF NRROS Variants Impairing Active TGF-β1 Delivery Cause a Severe Infantile-Onset Neurodegenerative Condition with Intracranial Calcification
AU - Dong, Xiaomin
AU - Tan, Natalie B.
AU - Howell, Katherine B.
AU - Barresi, Sabina
AU - Freeman, Jeremy L.
AU - Vecchio, Davide
AU - Piccione, Maria
AU - Radio, Francesca Clementina
AU - Calame, Daniel
AU - Zong, Shan
AU - Eggers, Stefanie
AU - Scheffer, Ingrid E.
AU - Tan, Tiong Y.
AU - Van Bergen, Nicole J.
AU - Tartaglia, Marco
AU - Christodoulou, John
AU - White, Susan M.
N1 - Funding Information:
We are grateful to the affected individuals and their family members for participating in this study. We thank Shahnaz Khan for providing the Calnexin antibody. We also thank Joseph Tam for his support with clinical information provided. The research conducted at the Murdoch Children’s Research Institute was supported by the Victorian Government’s Operational Infrastructure Support Program . We are grateful to the Harbig Foundation for generous financial support. N.T. acknowledges the Australian National Health and Medical Research Council (NHMRC) Centre for Research Excellence in Neurocognitive Disorders for their support. K.B.H. is supported by funding from the Australian NHMRC . M.T. acknowledges the Italian Ministry of Health ( Ricerca Corrente 2019 ) and Fondazione Bambino Gesù ( Vite Coraggiose ).
Funding Information:
We are grateful to the affected individuals and their family members for participating in this study. We thank Shahnaz Khan for providing the Calnexin antibody. We also thank Joseph Tam for his support with clinical information provided. The research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program. We are grateful to the Harbig Foundation for generous financial support. N.T. acknowledges the Australian National Health and Medical Research Council (NHMRC) Centre for Research Excellence in Neurocognitive Disorders for their support. K.B.H. is supported by funding from the Australian NHMRC. M.T. acknowledges the Italian Ministry of Health (Ricerca Corrente 2019) and Fondazione Bambino Ges? (Vite Coraggiose).
Publisher Copyright:
© 2020
PY - 2020/4/2
Y1 - 2020/4/2
N2 - 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.
AB - 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.
KW - intracranial calcification
KW - mutation
KW - neurodegeneration
KW - neuroinflammation
KW - NRROS
KW - TGF-β1
UR - http://www.scopus.com/inward/record.url?scp=85082426547&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85082426547&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2020.02.014
DO - 10.1016/j.ajhg.2020.02.014
M3 - Article
C2 - 32197075
AN - SCOPUS:85082426547
VL - 106
SP - 559
EP - 569
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 4
ER -