RESUMO
Usher syndrome type 1 describes the association of profound, congenital sensorineural deafness, vestibular hypofunction and childhood onset retinitis pigmentosa. It is an autosomal recessive condition and is subdivided on the basis of linkage analysis into types 1A through 1E. Usher type 1C maps to the region containing the genes ABCC8 and KCNJ11 (encoding components of ATP-sensitive K + (KATP) channels), which may be mutated in patients with hyperinsulinism. We identified three individuals from two consanguineous families with severe hyperinsulinism, profound congenital sensorineural deafness, enteropathy and renal tubular dysfunction. The molecular basis of the disorder is a homozygous 122-kb deletion of 11p14-15, which includes part of ABCC8 and overlaps with the locus for Usher syndrome type 1C and DFNB18. The centromeric boundary of this deletion includes part of a gene shown to be mutated in families with type 1C Usher syndrome, and is hence assigned the name USH1C. The pattern of expression of the USH1C protein is consistent with the clinical features exhibited by individuals with the contiguous gene deletion and with isolated Usher type 1C.
Assuntos
Proteínas de Transporte/genética , Perda Auditiva Neurossensorial/genética , Hiperinsulinismo/genética , Degeneração Retiniana/genética , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Sequência de Bases , Proteínas de Transporte/biossíntese , Proteínas de Ciclo Celular , Linhagem Celular , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 11 , Consanguinidade , Proteínas do Citoesqueleto , Análise Mutacional de DNA , Duodeno/metabolismo , Éxons , Olho/embriologia , Saúde da Família , Feminino , Deleção de Genes , Genes Recessivos , Ligação Genética , Humanos , Imuno-Histoquímica , Lactente , Íntrons , Canais Iônicos/genética , Túbulos Renais/anormalidades , Masculino , Dados de Sequência Molecular , Pâncreas/anormalidades , Linhagem , Splicing de RNA/genética , Retina/embriologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sitios de Sequências RotuladasRESUMO
Recent studies in mice have shown that pancreatic ß-cells have a significant potential for regeneration, suggesting that regenerative therapy for diabetes is feasible. Genetic lineage tracing studies indicate that ß-cell regeneration is based on the replication of fully differentiated, insulin-positive ß-cells. Thus, a major challenge for this field is to identify and enhance the molecular pathways that control ß-cell replication and mass. We review evidence, from human genetics and mouse models, that glucose is a major signal for ß-cell replication. The mitogenic effect of blood glucose is transmitted via glucose metabolism within ß-cells, and through a signalling cascade that resembles the pathway for glucose-stimulated insulin secretion. We introduce the concept that the individual ß-cell workload, defined as the amount of insulin that an individual ß-cell must secrete to maintain euglycaemia, is the primary determinant of replication, survival and mass. We also propose that a cell-autonomous pathway, similar to that regulating replication, appears to be responsible for at least some of the toxic effects of glucose on ß-cells. Understanding and uncoupling the mitogenic and toxic effects of glucose metabolism on ß-cells may allow for the development of effective regenerative therapies for diabetes.