SELECTED STUDIES
 

Section Editor: Prof. Talaat I. Farag

Chromosome 21

The Mystery of Down Syndrome

 By Prof. Alaa Eldin A. Elshafey

Chromosome 21 is the smallest human chromosome, spanning about 50 million base pairs and representing approximately 1.5 percent of the total DNA in cells and it was the second human chromosome to be fully sequenced. Because researchers use different approaches to predict the number of genes on each chromosome, the estimated number of genes varies and chromosome 21 likely contains between 200 and 400 genes. Most of these genes are linked to different kinds of disease conditions. The following figure summarizes some of these common diseases linked to chromosome 21. This article was the topic of a lecture given at the Maternity Hospital, Kuwait in May 2008.

 The Story of Down Syndrome

The formal story began in 1866 (John Langdon Down in Surrey, England) he referred to as "Mongoloids."   Down based this unfortunate name on his notion that these children looked like people from Mongolia, who were thought then to have an arrested development. This ethnic insult came under fire in the early 1960s from Asian genetic researchers. The condition became called "Down's syndrome”. In the 1970s, an American revision of scientific terms changed it simply to "Down syndrome," while it still is called "Down's" in the UK and some places in Europe.

In the first part of the twentieth century, there was much speculation of the cause of Down syndrome. The first to speculate that it might be due to chromosomal abnormalities were Waardenburg and Bleyer in the 1930s. In 1959 Jerome Lejeune and Patricia Jacobs, working independently, first determined the cause to be trisomy (triplication) of the 21st chromosome. Cases of Down syndrome due to translocation and mosaicism were described over the next three years. In Down syndrome, 95% of all cases are caused by non-disjunction. Cause of the non-disjunction error isn't known, but there is definitely connection with maternal age.

Between  3 and 4% of all cases of trisomy 21 are due to Robertsonian Translocation. In this case, the number of chromosomes remain normal. Some of these children may only have triplication of part of the 21st chromosome instead of the whole chromosome, which is called a partial trisomy 21. Translocations resulting in trisomy 21 may be inherited. All de novo t(14;21) trisomies studied have originated in maternal germ cells. The mean maternal age was 29.2 years. In de novo t(21;21) Down syndrome the situation is different. In most cases the t(21;21) is an isochromosome (dup21q) rather than the result of a Robertsonian translocation caused by a fusion between 2 heterologous chromatids. About half were of paternal and half of maternal origin.

The remainder of cases of trisomy 21 are due to mosaicism. These people have a mixture of cell lines, some of which have a normal set of chromosomes and others which have trisomy 21. In cellular mosaicism, the mixture is seen in different cells of the same type. In tissue mosaicism, one set of cells, such as all blood cells, may have normal chromosomes, and another type, such as all skin cells, may have trisomy 21.

The 21^st Chromosome genes and Down Syndrome

In trisomy 21, the presence of an extra set of genes leads to over-expression of the involved genes. For most genes, their over-expression has little effect due to the body's regulating mechanisms of genes and their products. But the genes that cause Down syndrome appear to be exceptions. Down syndrome critical regions (DCR), are regions on chromosome 21 which are associated with most of the clinical manifestations of Down syndrome when present in triplicate. A subregion (DCR2) between D21S55 and MX1 (interferon-induced protein p78), in 21q22.3, has been associated with mental retardation and several morphologic features of Down syndrome.

Genes that may have input into Down syndrome

These genes are suggested to be responsible for the phenotypes observed in Down syndrome patients. They are present, mostly, within Down syndrome critical regions. One of these genes is DSCR1; a highly expressed in brain and heart, and suggested as a candidate for involvement in the pathogenesis of DS, in particular mental retardation and/or cardiac defects (Fuentes et al.,1995). Other genes include, DSCR4 that map to the 1.6-Mb Down syndrome critical region and is predominantly expressed in placenta (Nakamura et al., 1997). DSCR2 (C21LRP; chromosome 21 leucine-rich protein) within DCR2.  The DSCR2 mRNA is detected in brain, colon, leukocytes, breast, and testis, as well as in all fetal tissues. Bahn et al., 2002 studied gene expression in neuronal precursor cells of Down syndrome. They found that genes regulated by the REST transcription factor were selectively repressed. One of these genes, SCG10, which encodes a neuron-specific growth-associated protein, was almost undetectable. The REST factor itself was also downregulated by 49% compared to controls. The authors suggested a link between dysregulation of REST and some of the neurologic deficits seen in Down syndrome.  

Genes outside DCR region may have input into DS. The list is huge and the following are some of these genes:

• Superoxide Dismutase (SOD1)-- over-expression may cause premature aging and decreased function of the immune system.

• COL6A1 -- over-expression may be the cause of heart defects.

• DYRK -- over-expression may be the cause of mental retardation.

• CRYA1 -- over-expression may be the cause of cataracts.

• IFNAR -- the gene for expression of Interferon, over-expression may interfere with the immune system as well as other organ systems.

• APP (Amyloid beta A4 precursor protein gene) suspected to have a major role in cognitive difficulties.

• Other genes that are also suspects include PAC1 (proteasome-assembling chaperone1), PAC2, GLUR5, S100B, TAM, PFKL, and a few others.

Again, it is important to note that no gene has yet been fully linked to any feature associated with Down syndrome.

One of the more notable aspects of Down syndrome is the wide variety of features and characteristics of people with trisomy 21. The first possible reason is the difference in the genes that are over-expressed. One other thing is that genes can come in different alternate forms "alleles". The effect of over-expression of genes may depend on which allele is present in the person with trisomy 21. Moreover, one allele may cause a condition to be present in some people but not others, what is called "variable penetrance“, and that appears to be what happens with trisomy 21: the alleles don't do the same thing to every person who has it (genes interacting with the genetic make up of the person).

Prandini et al. (2007) classified all genes in chromosome 21 into 3 groups: (A) non-overlapping, (B) partially overlapping, and (C) extensively overlapping expression distributions between normal and Down syndrome samples. In each cell type, group A genes are the most dosage-sensitive and are most likely involved in the constant DS traits; group B genes may be involved in variable DS traits; and group C genes are not dosage-sensitive (least likely to participate in DS phenotypes). Yahya-Graison et al (2007) reached a comparable classification of genes over-expression in DS. These classifications should have an impact on the search for genes that are involved in the DS phenotype.

What More?

It would be a mistake to assume that the clinical features of Down syndrome are only due to a handful of genes being over-expressed. You can think of the over-expressed gene products interacting with a number of normal gene products, each product individualized by the person's unique genetic makeup, and thus being thrown “out of genetic balance”. This would then make the person more susceptible to other genetic and environmental insults, leading to the features, diseases and conditions associated with Down syndrome. It is this complex arrangement that scientists will be addressing in the second century of Down syndrome research.

• Altafaj, X.; Dierssen, M.; Baamonde, C.; Marti, E.; Visa, J.; Guimera, J.; Oset, M.; Gonzalez, J. R.; Florez, J.; Fillat, C.; Estivill, X. : Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome. Hum. Molec. Genet. 10: 1915-1923, 2001.

• Bahn, S.; Mimmack, M.; Ryan, M.; Caldwell, M. A.; Jauniaux, E.; Starkey, M.; Svendsen, C. N.; Emson, P. : Neuronal target genes of the neuron-restrictive silencer factor in neurospheres derived from fetuses with Down's syndrome: a gene expression study. Lancet 359: 310-315, 2002.

• Brown, A. S.; Feingold, E.; Broman, K. W.; Sherman, S. L. : Genome-wide variation in recombination in female meiosis: a risk factor for non-disjunction of chromosome 21. Hum. Molec. Genet. 9: 515-523, 2000.

• Canzonetta, C.; Mulligan, C.; Deutsch, S.; Ruf, S.; O'Doherty, A.; Lyle, R.; Borel, C.; Lin-Marq, N.; Delom, F.; Groet, J.; Schnappauf, F.; De Vita, S; and 12 others : DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome. Am. J. Hum. Genet. 83: 388-400, 2008.

• Fuentes, J.-J.; Pritchard, M. A.; Planas, A. M.; Bosch, A.; Ferrer, I.; Estivill, X. : A new human gene from the Down syndrome critical region encodes a proline-rich protein highly expressed in fetal brain and heart. Hum. Molec. Genet. 4: 1935-1944, 1995.

• Gwack, Y.; Sharma, S.; Nardone, J.; Tanasa, B.; Iuga, A.; Srikanth, S.; Okamura, H.; Bolton, D.; Feske, S.; Hogan, P. G.; Rao, A. : A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT. Nature 441: 646-650, 2006.

• Hitzler, J. K.; Cheung, J.; Li, Y.; Scherer, S. W.; Zipursky, A. : GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome. Blood 101: 4301-4304, 2003.

• Korenberg, J.; Kawashima, H.; Pulst, S.; Ikeuchi, T.; Ogasawara, N.; Yamamoto, K.; Schonberg, S.; Kojis, T.; Allen, L.; Magenis, E.; Ikawa, H.; Taniguchi, N.; Epstein, C. : Molecular definition of the region of chromosome 21 that causes features of the Down syndrome phenotype. Am. J. Hum. Genet. 47: 236-246, 1990.

• Maslen, C.; Babcock, D.; Robinson, S. W.; Bean, L. J. H.; Dooley, K. J.; Willour, V. L.; Sherman, S. L. : CRELD1 mutations contribute to the occurrence of cardiac atrioventricular septal defects in Down syndrome. Am. J. Med. Genet. 140A: 2501-2505, 2006.

• Nakamura, A.; Hattori, M.; Sakaki, Y. : Isolation of a novel human gene from the Down syndrome critical region of chromosome 21q22.2. J. Biochem. 122: 872-877, 1997.

• Ohira, M.; Ichikawa, H.; Suzuki, E.; Iwaki, M.; Suzuki, K.; Saito-Ohara F.; Ikeuchi, T.; Chumakov, I.; Tanahashi, H.; Tashiro, K.; Sakaki, Y. : A 1.6-Mb P1-based physical map of the Down syndrome region on chromosome 21. Genomics 33: 65-74, 1996.

• Olson, L. E.; Richtsmeier, J. T.; Leszl, J.; Reeves, R. H. : A chromosome 21 critical region does not cause specific Down syndrome phenotypes. Science 306: 687-690, 2004.

• Prandini, P.; Deutsch, S.; Lyle, R.; Gagnebin, M.; Vivier, C. D.; Delorenzi, M.; Gehrig, C.; Descombes, P.; Sherman, S.; Bricarelli, F. D.; Baldo, C.; Novelli, A.; Dallapiccola, B.; Antonarakis, S. E. : Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance. Am. J. Hum. Genet. 81: 252-263, 2007.

• Taketani, T.; Taki, T.; Takita, J.; Ono, R.; Horikoshi, Y.; Kaneko, Y.; Sako, M.; Hanada, R.; Hongo, T.; Hayashi, Y. : Mutation of the AML1/RUNX1 gene in a transient myeloproliferative disorder patient with Down syndrome. (Letter) Leukemia 16: 1866-1867, 2002.

Dr. Alaa Eldin A. Elshafey, M.B.Ch.B.; M.Sc. (Ped).; Ph.D. (Genetics), is a senior molecular geneticist at the Kuwait Medical Genetics Center and Associate Professor of Genetics at Menoufiya University, Egypt. His email is aelshafey@yahoo.com.