The tricho-rhino-phalangeal syndrome type II (TRPS II, or Langer-Giedion syndrome) is an example of contiguous gene syndromes, as it comprises the clinical features of two autosomal dominant diseases, TRPS I and a form of multiple cartilaginous exostoses caused by mutations in the EXT1 gene. We have constructed a contig of cosmid, lambda-phage, PAC, and YAC clones, which covers the entire TRPS I critical region. Using these clones we identified a novel submicroscopic deletion in a TRPS I patient and refined the proximal border of the minimal TRPS1 gene region by precisely mapping the inversion breakpoint of another patient. As a first step towards a complete inventory of genes in the Langer-Giedion syndrome chromosome region (LGCR) with the ultimate aim to identify the TRPS1 gene, we analyzed 23 human expressed sequence tags (ESTs) and four genes (EIF3S3, RAD21, OPG, CXIV) which had been assigned to human 8q24.1. Our analyses indicate that the LGCR is gene-poor, because none of the ESTs and genes map to the minimal TRPS1 gene region and only two of these genes, RAD21 and EIF3S3, are located within the shortest region of deletion overlap of TRPS II patients. Two genes, OPG and CXIV, which are deleted only in some patients with TRPS II may contribute to the clinical variability of this syndrome.
We have mapped the gene encoding the p40 subunit of the eukaryotic translation initiation factor eIF3 (EIF3S3) close to the distal border of the minimal critical region for tricho-rhino-phalangeal syndrome type I (TRPS I) on human chromosome 8q24. Because this location makes EIF3S3 a candidate for the TRPS1 gene, we have determined the genomic structure of the EIF3S3 gene and searched for gene deletions and mutations in patients with TRPS I. The gene has eight exons and is transcribed from telomere to centromere. No deletion could be detected in 32 unrelated patients with an apparently normal karyotype. Sequence analysis of all exons in 15 unrelated patients did not reveal any point mutation either. Our data exclude EIF3S3 as the TRPS1 gene.
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