RESUMO
Amyotrophic lateral sclerosis (ALS) is a progressive, adult-onset, neurodegenerative disorder characterized by the death of large motor neurons from the cerebral cortex, brainstem, and spinal cord. The etiology of ALS remains unknown; however, approximately 10% of the cases are familial in nature. In the majority of these families, the mode of transmission is autosomal dominant. Recently, linkage of an autosomal dominant familial ALS (FALS) gene to the locus ALS1 on chromosome 21q was established. In addition, evidence was provided for genetic heterogeneity, with approximately 55% of families most likely linked to chromosome 21. The development of a number of highly informative simple sequence repeat polymorphisms in the region of linkage-21q21 through 21q22.1-has permitted us to confirm both the assignment of ALS1 to 21q and the genetic heterogeneity of FALS. In addition, we have been able to refine the mapping of ALS1, based on recombination events in two of the linked families. Flanking markers for the FALS gene are D21S213 on the centromeric side and D21S219 on the telomeric side. The candidate region is approximately 4 Mb and contains the genes copper/zinc superoxide dismutase (CuZnSOD); the fourth member of the class II cytokine receptor family (CRF2-4); and the interferon-alpha receptor (IFNAR).
Assuntos
Esclerose Lateral Amiotrófica/genética , Cromossomos Humanos Par 21 , Mapeamento Cromossômico , Ligação Genética/genética , Marcadores Genéticos , Haplótipos/genética , Humanos , Linhagem , Polimorfismo Genético/genéticaAssuntos
Carbono-Nitrogênio Ligases , Cromossomos Humanos Par 21 , Hidroximetil e Formil Transferases , Polimorfismo Genético , Sequências Repetitivas de Ácido Nucleico , Aciltransferases/genética , Alelos , Sequência de Bases , DNA/genética , Frequência do Gene , Humanos , Ligases/genética , Dados de Sequência Molecular , Complexos Multienzimáticos , Oligodesoxirribonucleotídeos/genética , Fosforribosilglicinamido FormiltransferaseRESUMO
Though the nature of the underlying metabolic defect which leads to amyotrophic lateral sclerosis (ALS) remains obscure, certain biochemical anomalies have been found, such as, reduced RNA content in ALS motor neurons. Recently, a gene causing the familial form of ALS (FALS) has been assigned to an interval of approximately 10 cM including the locus D21S58 on chromosome 21q22.1. This region includes the GART gene which encodes an enzyme catalyzing three steps in the de novo biosynthesis of purine nucleotides which are precursors for RNA. A defect of this gene might result in reduced RNA production and predispose to premature death of motor neurons. In order to test GART as a candidate we developed two highly informative DNA markers in this region and carried out linkage analyses for FALS. GART is excluded as a candidate for FALS.
