Syndrome Candidate Region Research Articles

Genomic Organization, Alternative Splicing, and Expression Patterns of theDSCR1(Down Syndrome Candidate Region 1) Gene

Down syndrome is a major cause of mental retardation and congenital heart defects and is due to the presence of three copies of human chromosome 21 in the affected individual. We have identified a gene,DSCR1(HGMW-approved symbol), from the region 21q22.1–q22.2, which is highly expressed in human fetal brain and adult heart. Structural features of the conceptual protein encourage us to propose involvement of DSCR1 in the regulation of transcription and/or signal transduction. Higher expression of RNA in the brains of young rats compared to adults suggests a possible role for the gene in the development of the central nervous system. We have determined the genomic organization ofDSCR1and identified three additional alternative first exons by RACE and cDNA library screening.DSCR1spans nearly 45 kb of genomic DNA and comprises seven exons, four of which (exons 1–4) are alternative first exons. All the exons are flanked by splice junctions that conform to the consensus AG-GT motif. We have studied the expression patterns of the alternative first exons. Exon 2 was detected in fetal brain and liver by RT-PCR. Both exons 1 and 4 were differentially expressed in fetal brain, lung, liver, and kidney and in all adult tissues tested by Northern analysis with two notable exceptions: exon 1 was not detected in adult kidney and exon 4 was not found in adult brain. The high level of expression of exon 1 in fetal brain suggests that this alternative form of DSCR1 has an important role in brain development. This information should help us to understand the possible relationship ofDSCR1with Down syndrome and aid in the development of animal models.

Cloning of the human heparan sulfate- N-deacetylase/ N-sulfotransferase gene from the treacher Collins syndrome candidate region at 5q32–q33.1

Treacher Collins syndrome is an autosomal dominant disorder of craniofacial development, the features of which include conductive hearing loss and cleft palate. Previous studies have shown that the Treacher Collins syndrome locus is flanked by D5S519 and SPARC, and a yeast artificial chromosome contig encompassing this “critical region” has been completed. In the current investigation a cosmid containing D5S519 has been used to screen a human placental cDNA library. This has resulted in the cloning of the human heparan sulfate- N-deacetylase/ N-sulfotransferase gene. Two different mRNA species that have identical protein coding sequences but that differ in the size and sequence of the 3′ untranslated regions (3′UTR) have been identified. The smaller species has a 3′ UTR of 1035 bp, whereas that of the larger is 4878 bp.