RESUMO
Early-onset torsion dystonia is a movement disorder, characterized by twisting muscle contractures, that begins in childhood. Symptoms are believed to result from altered neuronal communication in the basal ganglia. This study identifies the DYT1 gene on human chromosome 9q34 as being responsible for this dominant disease. Almost all cases of early-onset dystonia have a unique 3-bp deletion that appears to have arisen idependently in different ethnic populations. This deletion results in loss of one of a pair of glutamic-acid residues in a conserved region of a novel ATP-binding protein, termed torsinA. This protein has homologues in nematode, rat, mouse and humans, with some resemblance to the family of heat-shock proteins and Clp proteases.
Assuntos
Cromossomos Humanos Par 9 , Distonia Muscular Deformante/genética , Chaperonas Moleculares , Transportadores de Cassetes de Ligação de ATP/genética , Idade de Início , Sequência de Aminoácidos , Animais , Sequência de Bases , Proteínas de Transporte/química , Mapeamento Cromossômico , Análise Mutacional de DNA , Triagem de Portadores Genéticos , Ligação Genética , Marcadores Genéticos , Humanos , Judeus/genética , Linfócitos , Camundongos , Dados de Sequência Molecular , Mutação Puntual , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Ratos , Proteínas Recombinantes/biossíntese , Alinhamento de Sequência , Deleção de Sequência , Homologia de Sequência de Aminoácidos , Transcrição GênicaRESUMO
Familial, early onset, generalized torsion dystonia is the most common and severe primary dystonia. The majority of cases are caused by a 3-bp deletion (GAG) in the coding region of the DYT1 (TOR1A) gene. The cellular and regional distribution of torsinA protein, which is restricted to neuronal cells and present in all brain regions by the age of 2 months has been described recently in human developing brain. TorsinB is a member of the same family of proteins and is highly homologous with its gene adjacent to that for torsinA on chromosome 9q34. TorsinA and torsinB share several remarkable features suggesting that they may interact in vivo. This study examined the expression of torsinB in the human brain of fetuses, infants and children up to 7 years of age. Our results indicate that torsinB protein expression is temporarily and spatially regulated in a similar fashion as torsinA. Expression of torsinB protein was detectable beginning at four to 8 weeks of age in the cerebellum (Purkinje cells), substantia nigra (dopaminergic neurons), hippocampus and basal ganglia and was predominantly restricted to neuronal cells. In contrast to torsinA, torsinB immunoreactivity was found more readily in the nuclear envelope. High levels of torsinB protein were maintained throughout infancy, childhood and adulthood suggesting that torsinB is also needed for developmental events occurring in the early postnatal phase and is necessary for functional activity throughout life.
Assuntos
Química Encefálica/fisiologia , Encéfalo/crescimento & desenvolvimento , Chaperonas Moleculares/biossíntese , Neurônios/metabolismo , Adulto , Axônios/metabolismo , Gânglios da Base/metabolismo , Western Blotting , Cerebelo/metabolismo , Criança , Pré-Escolar , Citoplasma/metabolismo , Dendritos/metabolismo , Feminino , Hipocampo/metabolismo , Humanos , Imuno-Histoquímica , Lactente , Recém-Nascido , Masculino , Mesencéfalo/metabolismo , GravidezRESUMO
Familial, early onset, generalized torsion dystonia is the most common and severe primary dystonia. The majority of cases are caused by a 3-bp deletion (GAG) in the coding region of the DYT1 (TOR1A) gene. The cellular and regional distribution of torsinA protein and its message has been described previously in several regions of normal adult human and rodent brain. This study examines the expression of torsinA in the developing human brain of fetuses, infants and children up to 7 years of age in four selected brain regions. Expression of torsinA protein was detectable beginning at 4 to 8 weeks of age postnatally in the cerebellum (Purkinje cells), substantia nigra (dopaminergic neurons), hippocampus and basal ganglia. Prominent torsinA immunoreactivity was not seen before 6 weeks of age postnatally, a period associated with synaptic remodeling, process elimination and the beginning of myelination. Our results indicate that torsinA protein expression is temporally and spatially regulated and is present in all brain regions studied by the age of 2 months on into adulthood.
Assuntos
Encéfalo/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Chaperonas Moleculares/metabolismo , Adulto , Autorradiografia/métodos , Western Blotting/métodos , Encéfalo/anatomia & histologia , Encéfalo/crescimento & desenvolvimento , Criança , Pré-Escolar , Dopamina/metabolismo , Feminino , Feto , Idade Gestacional , Humanos , Imuno-Histoquímica/métodos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Chaperonas Moleculares/genética , Neurônios/metabolismo , Reação em Cadeia da Polimerase/métodosAssuntos
Proteínas de Transporte/genética , Distonia Muscular Deformante/genética , Proteínas de Choque Térmico/genética , Chaperonas Moleculares , Serina Endopeptidases/genética , Adenosina Trifosfatases/genética , Idade de Início , Mapeamento Cromossômico , Endopeptidase Clp , Humanos , Dados de Sequência Molecular , Homologia de Sequência de AminoácidosRESUMO
Most cases of early onset torsion dystonia are caused by a 3-bp deletion (GAG) in the coding region of the TOR1A gene (alias DYT1, DQ2), resulting in loss of a glutamic acid in the carboxy terminal of the encoded protein, torsin A. TOR1A and its homologue TOR1B (alias DQ1) are located adjacent to each other on human chromosome 9q34. Both genes comprise five similar exons; each gene spans a 10-kb region. Mutational analysis of most of the coding region and splice junctions of TOR1A and TOR1B did not reveal additional mutations in typical early onset cases lacking the GAG deletion (N = 17), in dystonic individuals with apparent homozygosity in the 9q34 chromosomal region (N = 5), or in a representative Ashkenazic Jewish individual with late onset dystonia, who shared a common haplotype in the 9q34 region with other late onset individuals in this ethnic group. A database search revealed a family of nine related genes (50-70% similarity) and their orthologues in species including human, mouse, rat, pig, zebrafish, fruitfly, and nematode. At least four of these genes occur in the human genome. Proteins encoded by this gene family share functional domains with the AAA/HSP/Clp-ATPase superfamily of chaperone-like proteins, but appear to represent a distinct evolutionary branch.