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Structural basis for the dominant or recessive character of GLIALCAM mutations found in leukodystrophies.
Elorza-Vidal, Xabier; Xicoy-Espaulella, Efren; Pla-Casillanis, Adrià; Alonso-Gardón, Marta; Gaitán-Peñas, Héctor; Engel-Pizcueta, Carolyn; Fernández-Recio, Juan; Estévez, Raúl.
Afiliação
  • Elorza-Vidal X; Unitat de Fisiologia, Departament de Ciències Fisiològiques, Genes Disease and Therapy Program IDIBELL-Institute of Neurosciences, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain.
  • Xicoy-Espaulella E; Centro de Investigación en red de enfermedades raras (CIBERER), ISCIII, Madrid, Spain.
  • Pla-Casillanis A; Unitat de Fisiologia, Departament de Ciències Fisiològiques, Genes Disease and Therapy Program IDIBELL-Institute of Neurosciences, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain.
  • Alonso-Gardón M; Unitat de Fisiologia, Departament de Ciències Fisiològiques, Genes Disease and Therapy Program IDIBELL-Institute of Neurosciences, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain.
  • Gaitán-Peñas H; Unitat de Fisiologia, Departament de Ciències Fisiològiques, Genes Disease and Therapy Program IDIBELL-Institute of Neurosciences, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain.
  • Engel-Pizcueta C; Unitat de Fisiologia, Departament de Ciències Fisiològiques, Genes Disease and Therapy Program IDIBELL-Institute of Neurosciences, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain.
  • Fernández-Recio J; Centro de Investigación en red de enfermedades raras (CIBERER), ISCIII, Madrid, Spain.
  • Estévez R; Unitat de Fisiologia, Departament de Ciències Fisiològiques, Genes Disease and Therapy Program IDIBELL-Institute of Neurosciences, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain.
Hum Mol Genet ; 29(7): 1107-1120, 2020 05 08.
Article em En | MEDLINE | ID: mdl-31960914
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Conformação Proteica / Encéfalo / Proteínas de Ciclo Celular / Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central / Cistos / Proteínas de Membrana Limite: Humans Idioma: En Revista: Hum Mol Genet Assunto da revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Espanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Conformação Proteica / Encéfalo / Proteínas de Ciclo Celular / Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central / Cistos / Proteínas de Membrana Limite: Humans Idioma: En Revista: Hum Mol Genet Assunto da revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Espanha