RESUMO
We recently identified mutations of ARX in nine genotypic males with X-linked lissencephaly with abnormal genitalia (XLAG), and in several female relatives with isolated agenesis of the corpus callosum (ACC). We now report 13 novel and two recurrent mutations of ARX, and one nucleotide change of uncertain significance in 20 genotypic males from 16 families. Most had XLAG, but two had hydranencephaly and abnormal genitalia, and three males from one family had Proud syndrome or ACC with abnormal genitalia. We obtained detailed clinical information on all 29 affected males, including the nine previously reported subjects. Premature termination mutations consisting of large deletions, frameshifts, nonsense mutations, and splice site mutations in exons 1 to 4 caused XLAG or hydranencephaly with abnormal genitalia. Nonconservative missense mutations within the homeobox caused less severe XLAG, while conservative substitution in the homeodomain caused Proud syndrome. A nonconservative missense mutation near the C-terminal aristaless domain caused unusually severe XLAG with microcephaly and mild cerebellar hypoplasia. In addition, several less severe phenotypes without malformations have been reported, including mental retardation with cryptogenic infantile spasms (West syndrome), other seizure types, dystonia or autism, and nonsyndromic mental retardation. The ARX mutations associated with these phenotypes have included polyalanine expansions or duplications, missense mutations, and one deletion of exon 5. Together, the group of phenotypes associated with ARX mutations demonstrates remarkable pleiotropy, but also comprises a nearly continuous series of developmental disorders that begins with hydranencephaly, lissencephaly, and agenesis of the corpus callosum, and ends with a series of overlapping syndromes with apparently normal brain structure.
Assuntos
Regulação da Expressão Gênica/genética , Proteínas de Homeodomínio/genética , Mutação/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Agenesia do Corpo Caloso , Células Cultivadas , Corpo Caloso/patologia , Análise Mutacional de DNA/métodos , Feminino , Ligação Genética/genética , Genitália Feminina/anormalidades , Genitália Feminina/patologia , Genitália Masculina/anormalidades , Genitália Masculina/patologia , Genótipo , Proteínas de Homeodomínio/biossíntese , Humanos , Recém-Nascido , Linfócitos/química , Linfócitos/metabolismo , Linfócitos/patologia , Imageamento por Ressonância Magnética , Masculino , Mutação de Sentido Incorreto/genética , Linhagem , Fenótipo , Transtornos dos Cromossomos Sexuais/genética , Fatores de Transcrição/biossínteseRESUMO
The purpose of the study is to outline a computational architecture for the intelligent processing of sensorimotor patterns. The focus is on the nature of the internal representations of the outside world which are necessary for planning and other goal-oriented functions. A model of cortical map dynamics and self-organization is proposed that integrates a number of concepts and methods partly explored in the field. The novelty and the biological plausibility is related to the global architecture which allows one to deal with sensorimotor patterns in a coordinate-free way, using population codes as distributed internal representations of external variables and the coupled dynamics of cortical maps as a general tool of trajectory formation. The basic computational features of the model are demonstrated in the case of articulatory speech synthesis and some of the metric properties are evaluated by means of simple simulation studies.