RESUMO
The deleted in colorectal cancer (DCC) gene encodes the netrin-1 (NTN1) receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline DCC mutations disrupt the development of predominantly commissural tracts in the central nervous system (CNS) and cause a spectrum of neurological disorders. Monoallelic, missense, and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum (ACC), or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome (DSBS). Although the underlying molecular mechanisms leading to disease remain poorly understood, they are thought to stem from reduced or perturbed NTN1 signaling. Here, we review the 26 reported DCC mutations associated with abnormal CNS development in humans, including 14 missense and 12 predicted loss-of-function mutations, and discuss their associated clinical characteristics and diagnostic features. We provide an update on the observed genotype-phenotype relationships of congenital mirror movements, isolated ACC and DSBS, and correlate this to our current understanding of the biological function of DCC in the development of the CNS. All mutations and their associated phenotypes were deposited into a locus-specific LOVD (https://databases.lovd.nl/shared/genes/DCC).
Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Genes DCC , Estudos de Associação Genética , Mutação , Fenótipo , Agenesia do Corpo Caloso , Sequência de Aminoácidos , Sítios de Ligação , Sequência Conservada , Bases de Dados Genéticas , Humanos , Imageamento por Ressonância Magnética , Modelos Moleculares , Netrina-1/química , Netrina-1/metabolismo , Ligação Proteica , Conformação Proteica , Domínios Proteicos/genética , SíndromeRESUMO
Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual.
Assuntos
Agenesia do Corpo Caloso/genética , Deficiências do Desenvolvimento/genética , Mutação/genética , Receptores de Superfície Celular/genética , Proteínas Supressoras de Tumor/genética , Anormalidades Múltiplas/genética , Encéfalo/patologia , Corpo Caloso/patologia , Receptor DCC , Família , Feminino , Humanos , Masculino , Malformações do Sistema Nervoso/genética , Células-Tronco Neurais/patologia , Penetrância , FenótipoRESUMO
Truncating mutations in the SPG11 and SPG15 genes cause complicated spastic paraplegia, severe neurological conditions due to loss of the functions of spatacsin and spastizin, respectively. We developed specific polyclonal anti-spatacsin (SPG11) and anti-spastizin (SPG15) antisera, which we then used to explore the intracellular and tissue localizations of these proteins. We observed expression of both proteins in human and rat central nervous system, which was particularly strong in cortical and spinal motor neurons as well as in retina. Both proteins were also expressed ubiquitously and strongly in embryos. In cultured cells, these two proteins had similar diffuse punctate, cytoplasmic and sometimes nuclear (spastizin) distributions. They partially co-localized with multiple organelles, particularly with protein-trafficking vesicles, endoplasmic reticulum and microtubules. Spastizin was also found at the mitochondria surface. This first study of the endogenous expression of spatacsin and spastizin shows similarities in their expression patterns that could account for their overlapping clinical phenotypes and involvement in a common protein complex.