Down syndrome--a gene dosage disease caused by trisomy of genes within a small segment of the long arm of chromosome 21, exemplified by the study of effects from the superoxide-dismutase type 1 (SOD-1) gene.

Down syndrome (DS), the most common postnatally viable human autosomal chromosomal abnormality is caused by trisomy for chromosome 21. The mechanism whereby the supernumerary chromosome 21 contributes to the pathology of DS remains elusive. There are, however, several evidences that DS is a gene dosage disease. This means that overproduction of certain proteins, encoded by normal genes on the extra chromosome, distorts the delicate balance of some biochemical pathways that are important for proper development and function of the organs affected in DS. It has been shown that only the distal segment of the long arm of chromosome 21 is involved in the pathogenesis of DS. Great efforts to define this "DS specific" segment are made today, with the aim to find the "DS responsible" genes. It is suggested that as few as 10-20 genes might be responsible for the DS phenotype. We will report from a world-wide collaboration study and especially the result from one single patient. It is a woman with a characteristic phenotype of DS, but with microscopically normal karyotype. She had a sister with DS, who is dead. The parents were related, why an autosomal recessive disorder is suspected. Autoradiograms of quantitative Southern blots of DNAs from the patient and her parents were analyzed after hybridization with unique DNA sequences regionally mapped on chromosome 21. The patient seems to have three alleles at the VTNR-polymorphism in the Col6A1 gene, one copy from the father and two copies from the mother. The Col6A1 gene is mapped at the very distal segment of the long arm of chromosome 21 (21q22.3). She has only two alleles of all loci analyzed proximal to Col6A1. This might indicate that she has trisomy only for the very distal part of band 21q22.3. It is, however, not enough to find the genes within the "DS specific" segment. The metabolic gene dosage effects from these genes must be evaluated. Although several genes have been mapped on chromosome 21, not one single feature of DS has been proved to be an effect of any single gene. As an example of the difficulties to assign features of DS to chromosome 21 specific genes the gene dosage effects of the superoxide dismutase type I (SOD-1) will be presented.