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Diagnosing Down Syndrome, Cystic Fibrosis, Tay-Sachs Disease And Other Genetic Disorders
Sometimes, a pediatrician will suspect that a child has a genetic disorder based on the child's symptoms or on the presence of dysmorphic features. For example, if a child has coarse facial features and developmental delays, a pediatrician may have reason to believe that the child has a form of mucopolysaccharidosis. Mucopolysaccharidosis is a family of diseases caused by an enzyme deficiency that leads to the accumulation of glycosaminoglycans (GAGs) within the lysosomes of cells. In one particular variant of this disease known as mucopolysaccharidosis I (MPS I), a deficiency of the enzyme alpha-L-iduronidase causes a build up of GAGs in tissues and organs, which in turn leads to a host of signs including skeletal deformities, coarse facial features, enlarged liver and spleen, and mental deficiencies. Because of the progressive nature of MPS I, a child might not exhibit noticeable symptoms until one to three years of age or even later, depending on severity.
There are a number of reasons that a pediatrician might refer a child to see a geneticist. Geneticists can confirm or rule out a physician's diagnosis based on the findings of a physical exam and various tests. In the case of a child with suspected MPS, if the enzymatic deficiency associated with the disorder is confirmed via testing, DNA analysis may also be performed to determine the exact genetic mutation causing the disorder. Because MPS I is inherited in an autosomal recessive fashion, identification of the mutation can allow the family to undergo carrier screening, as well as prenatal or preimplantation diagnosis in any future children.Trisomy 21 Causes Down Syndrome
One could argue that the presence of extra copies of chromosome 21 in DS patients is only a correlation between an abnormality and the disease. However, scientists have developed trisomic mouse models that display symptoms of human DS, providing strong evidence that extra copies of chromosome 21 are, indeed, responsible for DS. It is possible to construct mouse models of DS because mouse chromosomes contain several regions that are syntenic with regions on human chromosome 21. (Syntenic regions are chromosomal regions in two different species that contain the same linear order of genes.) With mapping of the human and mouse genomes now complete, researchers can identify syntenic regions in mouse and human chromosomes with great precision.
As shown in Figure 4, regions on the arms of mouse chromosomes 10 (MMU10), 16 (MMU16), and 17 (MMU17) are syntenic with regions on the long q arm of human chromosome 21. Using some genetic tricks, scientists have induced translocations involving these mouse chromosomes, producing mice that are trisomic for regions suspected to play a role in DS. (Note that these are not perfect models, because the trisomic regions contain many mouse genes in addition to those that are syntenic to human chromosome 21 genes.) These experiments have shown that genes from MMU16 are probably most important in DS, because mice carrying translocations from MMU16 display symptoms more like human DS than mice carrying translocations of MMU10 or MMU17.
Additional experiments have tried to identify particularly important genes within this region by transferring smaller segments of the interval on MMU16. For example, the three mouse models depicted on the right in Figure 4 carry different portions of MMU16, and all display some symptoms of DS. Of the three, the most faithful model of DS is the Ts65Dn mouse, which carries 132 genes that are syntenic with human chromosome 21. This particular mouse demonstrates many of the symptoms of human DS, including altered facial characteristics, memory and learning problems, and age-related changes in the forebrain.
These results are both daunting and promising. On one hand, they suggest that there will be no magic bullet for treating DS, because large numbers of genes are most likely involved in the condition. On the other hand, the results suggest that mouse models will be useful in developing treatments for the many DS patients around the world.
Figure 4: Regions of synteny between human chromosome 21 (HSA21) and mouse chromosomes (MMUs) 16, 17, and 10.
There are three partial trisomy mouse models of human trisomy 21, all trisomic for a portion of MMU 16. The gene content of these partial trisomies is shown on the right.
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