RESUMEN
Knobloch syndrome (KS) is a rare disease characterized by severe ocular alterations, including vitreoretinal degeneration associated with retinal detachment and occipital scalp defect. The responsible gene, COL18A1, has been mapped to 21q22.3, and, on the basis of the analysis of one family, we have demonstrated that a mutation affecting only one of the three COL18A1 isoforms causes this phenotype. We report here the results of the screening of both the entire coding region and the exon-intron boundaries of the COL18A1 gene (which includes 43 exons), in eight unrelated patients with KS. Besides 20 polymorphic changes, we identified 6 different pathogenic changes in both alleles of five unrelated patients with KS (three compound heterozygotes and two homozygotes). All are truncating mutations leading to deficiency of one or all collagen XVIII isoforms and endostatin. We have verified that, in exon 41, the deletion c3514-3515delCT, found in three unrelated alleles, is embedded in different haplotypes, suggesting that this mutation has occurred more than once. In addition, our results provide evidence of nonallelic genetic heterogeneity in KS. We also show that the longest human isoform (NC11-728) is expressed in several tissues (including the human eye) and that lack of either the short variant or all of the collagen XVIII isoforms causes similar phenotypes but that those patients who lack all forms present more-severe ocular alterations. Despite the small sample size, we found low endostatin plasma levels in those patients with mutations leading to deficiency of all isoforms; in addition, it seems that absence of all collagen XVIII isoforms causes predisposition to epilepsy.
Asunto(s)
Colágeno/genética , Anomalías del Ojo/genética , Heterogeneidad Genética , Mutación/genética , Fragmentos de Péptidos/genética , Degeneración Retiniana/genética , Desprendimiento de Retina/genética , Adolescente , Adulto , Niño , Preescolar , Colágeno/sangre , Colágeno Tipo XVIII , Endostatinas , Exones/genética , Femenino , Haplotipos/genética , Humanos , Lactante , Recién Nacido , Intrones/genética , Masculino , Datos de Secuencia Molecular , Linaje , Fragmentos de Péptidos/sangre , Fenotipo , Polimorfismo Genético/genética , Isoformas de Proteínas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , SíndromeRESUMEN
We report here a comparison of serum endostatin levels in Down syndrome patients to normal control subjects. We analysed serum samples from 35 patients with Down syndrome and 54 normal control subjects and found that although serum levels of endostatin vary widely in a normal human population, serum endostatin levels are significantly elevated in patients with Down syndrome. This result may explain the relative decrease in incidence of various solid tissue tumours observed in Down syndrome, given the role of endostatin as a potent inhibitor of tumour-induced angiogenesis in both human and animal models. Based upon these data, we propose that an increase of about one-third of normal endostatin serum levels may represent an effective therapeutic dose to significantly inhibit many solid tumours.