Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/173635
Title: Structural basis for the dominant or recessive character of GLIALCAM mutations found in leukodystrophies
Author: Elorza Vidal, Xabier
Xicoy Espaulella, Efren
Pla Casillanis, Adrià
Alonso Gardón, Marta
Gaitán-Peñas, Héctor
Engel Pizcueta, Carolyn
Fernández Recio, Juan
Estévez Povedano, Raúl
Keywords: Malalties cerebrals
Malalties hereditàries
Brain diseases
Genetic disorders
Issue Date: 1-Apr-2020
Publisher: Oxford University Press
Abstract: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a type of leukodystrophy characterized by white matter edema, and it is caused mainly by recessive mutations in MLC1 and GLIALCAM genes. These variants are called MLC1 and MLC2A with both types of patients sharing the same clinical phenotype. In addition, dominant mutations in GLIALCAM have also been identified in a subtype of MLC patients with a remitting phenotype. This variant has been named MLC2B. GLIALCAM encodes for an adhesion protein containing two immunoglobulin (Ig) domains and it is needed for MLC1 targeting to astrocyte-astrocyte junctions. Most mutations identified in GLIALCAM abolish GlialCAM targeting to junctions. However, it is unclear why some mutations behave as recessive or dominant. Here, we used a combination of biochemistry methods with a new developed anti-GlialCAM nanobody, double-mutants and cysteine cross-links experiments, together with computer docking, to create a structural model of GlialCAM homo-interactions. Using this model, we suggest that dominant mutations affect different GlialCAM-GlialCAM interacting surfaces in the first Ig domain, which can occur between GlialCAM molecules present in the same cell (cis) or present in neighbouring cells (trans). Our results provide a framework that can be used to understand the molecular basis of pathogenesis of all identified GLIALCAM mutations.
Note: Reproducció del document publicat a: https://doi.org/10.1093/hmg/ddaa009
It is part of: Human Molecular Genetics, 2020, vol. 29, num. 7, p. 1107-1120
URI: http://hdl.handle.net/2445/173635
Related resource: https://doi.org/10.1093/hmg/ddaa009
Appears in Collections:Articles publicats en revistes (Ciències Fisiològiques)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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