Journal article

Bi-allelic LoF NRROS Variants Impairing Active TGF-beta 1 Delivery Cause a Severe Infantile-Onset Neuro degenerative Condition with Intracranial Calcification

Xiaomin Dong, Natalie B Tan, Katherine B Howell, Sabina Barresi, Jeremy L Freeman, Davide Vecchio, Maria Piccione, Francesca Clementina Radio, Daniel Calame, Shan Zong, Stefanie Eggers, Ingrid E Scheffer, Tiong Y Tan, Nicole J Van Bergen, Marco Tartaglia, John Christodoulou, Susan M White

The American Journal of Human Genetics | CELL PRESS | Published : 2020

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 yea..

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Grants

Funding Acknowledgements

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 theMurdoch 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 andMedical 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 Gesu (Vite Coraggiose).