L. E. Maroun 143

Down Syndrome Research and Practice Vol. 5, No. 3, pp 143 - 147 © The Educational Trust Printed in Great Britain. All Rights Reserved. ISSN: 0968-7912 (1998) 5:3

THE UNTOWARD SIDE EFFECTS OF THERAPY CORRELATE WELL WITH THE SPECTRUM OF SYMPTOMS THAT MAKE UP THE DOWN SYNDROME

L.E. Maroun*, T. Heffernan, and D. Hallam *

Southern Illinois University School of Medicine

There is an ongoing effort to identify individual on that may independently each subserve one of the many diverse symptoms that constitute the Down syndrome. In contrast, the interferon system points to a multigene, multilocus, system distributed across Chromosome 21 that can explain each of the individual symptoms of the Down syndrome as a consequence of the concerted action of multiple genes which share in common a role in interferon action. To date, at least ten such genes have been identified on Chromosome 21. This number is likely to grow as new genes are identified, and their role in interferon action is uncovered. The recently discovered human SIM2 is presented here as an example. Its Intron 3 sequence reveals a clustering of interferon response elements that suggests an unexpected role for this gene in interferon action.

We also present here a comparative analysis of the complex of untoward side effects of interferon therapy that reveals a striking similarity to the spectrum of symptoms that make up the Down syndrome. Taken together, these gene mapping and clinical observations suggest the possibility that the diverse symptoms of the Down syndrome could have a surprisingly non-diverse underlying biochemistry.

Keywords: Down syndrome, interferon side effects

* From a paper presented at the 6th World Congress on Down Syndrome, Madrid, Spain, October 1997.

Introduction The “distal” half of chromosome 21 contains a It has been known for many years that cells from large cluster of genes that direct the synthesis of individuals with Down Syndrome are excessively interferon receptors and receptor components. sensitive to interferon effects (Tan et al., 1974). These genes control sensitivity to each of the Two observations suggest that this interferon various types of . In addition, the hypersensitivity could underlie many Down same “Down Syndrome Region” (DSR) contains Syndrome pathologies: genes whose activities are controlled by the interferons and at least one gene that is involved Numerous genes involved in interferon action in this control mechanism (ETS-2, a are located in the region of human chromosome “ factor”). These genes, along with 21 responsible for most of the Down Syndrome their potential role in brain function, have been pathologies. described previously (Maroun, 1996). ...28256.catatcgatgatgttgtttggaggtacaagacctaaTCCTTTCACTTTTGAaata |_____ISRE_____| aagacaaaagacaacataattatgtttgttgacataacttgaaccctgaaacccaaaccatctt gttttaaaatccttaatttaccatactcagcaaaacaccccagagtaacgtgcattttcagagt gccaagcaactctccccttccacacagaatatatgcatttagtgctgtatttatcatgtgtagg tttcttggcaagaagaaaagctattcagcaaaacataaaaaagctcttagtaggaaagctatcc attttgtagttagcagggttttgcaaatactaaaatatcacatggaaggtctgttttaataagg ctgatgcatgagacccagggagttttatagcgacaaccataattttttttttttttgtgaggta gtcacatttctctcagtgttcaaaagcgtggatagatacgtaaatacaggaaacaccatgtcaa ccataattttgacttaaggtcaggactgttttatcattccaaaatttgttcgtaaagacatttc cgttatttgaaggctgtttcacttcctagacagctctggagttttcccgttcgttttgtcacag actcgagccttcagaaaaccaagcctttcatctgtgcaacctcacccttctcattcttcaaaag catgtgttgagaacgggaactctgaaaacataagaacctactctgggattaaaacgcaaatcta acccttaataagcacagatggaaggtctttctgcaaggaggtaaagttgtttcccgaaaacaca tcagttacttttttccagaaaagaacttcgagcaaaccagaattattcttTTTCCCTGAAAaca |____GAS____| tggggaagggagaaacgataggccaatataacatttctctattttgttatttTTTCATTTTTAA |____ISRE____| aataaactgttgaaattgtgagtcactatatattt29242...

Figure 1. Interferon Response Elements in Intron 3 of the Human Chromosome 21 SIM2 Gene. (ISRE: Interferon Stimulated Response Element; GAS: Gamma [Interferon] Activated Sequence [Kalvakolanu and Borden, 1996]). Sequence data from: GenBank Locus HUMQ16F8.

Other genes mapped to Chromosome 21 and given interferon’s anticellular effects, the brain, thought to be important in brain function are heart and immune system function effects are also candidate interferon responsive genes. For surprising in their similarity to the pathology example, we have now found an unusual cluster seen in the Down syndrome. It is possible that of interferon response elements in Intron 3 of interferon’s ability to slow cell growth may the human SIM2 gene (Figure 1). subserve each of these pathologies at their most fundamental level. The presence on Chromosome 21 of genes that are targets of interferon action provides an This comparison is presented in tabular form attractive explanation of the many-fold increase in Table 1 along with pertinent references. in interferon sensitivity seen in cells from people with Down syndrome in spite of the observation Anti-interferons can reverse or prevent of only a fifty percent increase in interferon the untoward effects of the interferons. receptor numbers (Epstein, 1986). Because interferons can do so many apparently unrelated things, it has been traditional to A clear correlation is observed for many of demonstrate that a newly found biological the pathologies seen in a person with Down activity was indeed due to interferon by reversing syndrome with the side effects seen in patients or preventing the effect of added interferon by undergoing interferon therapy. simultaneously adding anti-interferon (usually an antibody) to the culture media. In all cases One of the most compelling arguments for the where the effect was due to the added involvement of interferon action in the Down interferon, the effect was, as would be expected, syndrome is based on a remarkable similarity of reversed or prevented by the anti-interferon the spectrum of symptoms seen in Down treatment. This ability of an anti-interferon to syndrome and with those seen in patients who reverse or prevent interferon actions has been have been treated with interferon. Although the extended to include “in vivo” whole animal effects of interferon on growth were predictable L. E. Maroun 145

Down Syndrome Pathologies Interferon Side Effects Learning Difficulties (Carr, 1985) Neurotoxicity (Mattson et al., 1983), Memory Loss (Iivanainen et al., 1985) Small frontal lobes (Wisniewski et.al., 1985) Frontal lobe encephalopathy (Mattson et al., 1984) Heart Pathology (Sei et al., 1995) Cardiotoxicity (Sonnenblick and Rosin, 1991) Arrhythmia (Martino et al., 1987) Leukopenia (Cossarizza et al., 1990) Leukopenia (Quesada et al., 1986) Autoimmune disease (Levo, 1977) Autoimmune disease (Burman et al., 1985) Hypothyroidism (Mitchell et al., 1994) Hypothyroidism (Fentiman et al., 1985) Hearing Loss (Roizen et al., 1992) Deafness (Kanda et al., 1995) Short Stature (Piro et al., 1990) Growth Inhibition (Kikawa et al., 1995) Table 1. A comparable spectrum of anomalies are seen in both Down syndrome and interferon-treated patients. observations including the extension of these a mutation in their interferon receptor genes observations to the animal model for Down (Newport et al., 1996) (Jouanguy et al., 1996). syndrome (Maroun, 1995). Injection of anti- Patients who have circulating anti-interferon interferon immunoglobins into mothers carrying antibodies as a consequence of interferon therapy trisomy 16 mouse fetuses resulted in significant show the expected decrease in the efficacy of return-to-normal values for fetal growth, eye further interferon treatment but no other closure, and back curvature (Maroun, 1995). In untoward effects have yet been observed contrast to the unpredictable growth of the (Quesada et al., 1986). Taken together, the untreated trisomy fetuses, the growth of the observations discussed here suggest that the in treated trisomy fetuses was essentially keeping vivo neutralization of interferon in individuals pace with that of their euploid littermates with Down Syndrome could be both safe and (Figure 2). potentially beneficial.

anti-IFN Acknowledgements treated This project was supported in part by the American Heart Association and the Excellence 24 trisomy in Academic Medicine program of Southern Illinois University School of Medicine. 22 Correspondence: 20 L.E. Maroun, Ph.D. Southern Illinois University normal littermates untreated School of Medicine. Dept. of Medical trisomy Microbiology/Immunology. P.O. Box 19230, 18 Springfield, Illinois USA 62794-1220. (Tel: (217) 785-2181, Fax: (217) 524-3227, 16 E-mail: [email protected])

Trisomy embryo length (mm) Trisomy 14

18 20 22 24 26 28 Normal littermate length (mm) Trisomy mouse embryo growth Figure 2. Improvement in the growth of trisomic mouse embryos treated with anti-IFN antibodies. Modified from Maroun, 1995.

In these experiments the reduction in interferon bioactivity was observed to be well tolerated. This is consistent with what is observed with “Knockout” mice whose genes for interferon receptors have been rendered inactive (Hwang et al., 1995). The same is true in humans who carry References

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