INVESTIGATION OF HUMAN DISEASE - Essay Example

Alternatively, a shorted dystrophin gene may be expressed but still different from normal due to an altered molecular weight. Different probes against different parts of the gene, or alternatively gene sequencing, can be exploited to identify the missing parts. Given the almost asymptomatic patient's status, likely due to the young age, no histological features are expected in muscle biopsies. Therefore, a molecular, i.e. immuno-histochemical, analysis will be necessary. Indeed, immunofluorescence (IF) analysis for dystrophin can confirm the genotyping.

In physiological conditions, laminin is localized around all muscle fibers and it appears as circles/polygonal shapes in muscle cross-sections, while it is absent in virtually all muscle fibers in diseased individuals (with the notable exception of possible revertant fibers). Given the invasive nature of this procedure, the IF analysis, which requires more tissue to be collected, will be performed as a second option and only in the presence of positive genetic tests. On examining the genomic DNA it was found that exon 52 was absent. (b) Will splicing of exon 51 to 53 produce a functional shortened dystrophin?

Explain and justify your decision by using an illustration and text (20%). The splicing of exon 51 to 53 does not produce a shortened dystrophin, since the two exons have different codon boundary. The result of the exon 52 deletion, is thus disruption of the genetic code and the premature stop of protein translation. On the contrary, the splicing of exon 51 to 54 would give rise to a shortened but functional form of dystrophin (see diagram below). In the case presented above, the absence of dystrophin expression and the development of DMD is the diagnosis.

Scheme of exon boundary extremities in the dystophin region of interest: After genetic counselling the parents choose to seek help from a specialist in gene therapy. (c) If you were the gene therapy specialist what kind of therapy would you suggest for the boy. Justify your choice. (20%) I would suggest an exon skipping approach with antisense oligonucleotides (AON) aimed to skip exon 53. The loss of the latter in addition to the congenital loss of exon 52 will likely allow to rescue the expression of an almost normal dystrophin, which lacks only two of the repeated motifs that constitute the central body of the protein.

Exon skipping has recently been proven an efficient therapeutic approach in large animals (dogs) affected by muscular dystrophy (Yokoda, 2011). PART II (50% total) 1) The picture above shows a family with an inherited disorder. All affected individuals are tall and thin, with long fingers and toes. a) What would a genetic counselor be able to tell an affected individual about the mode of inheritance and the serious complications associated with the disorder (10%) The phenotype of the people in the picture is compatible with the diagnosis of the Marfan.

In fact, people with Marfan syndrome tend to be unusually tall, with long, thin fingers. It is inherited as a dominant trait, thus people who have inherited one affected gene from either parent will have Marfan syndrome. This may explain the high penetrance of the disease into a group of individuals, likely members of the same family in the pcture. b) Explain the molecular basis of the condition (15%)