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Hemophilia

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Hemophilia A is an X-linked, recessive, bleeding disorder caused by a deficiency in the activity of coagulation factor VIII. Factor VIII (F8) is the protein product of the HEMA gene, located at map position Xq28. Affected individuals have internal bleeding in joints and muscles, easy bruising, and prolonged bleeding from wounds. It affects approximately 1 in 10,000 males in most populations (a similar number of females are carriers). There are about 17,000 people presently living with hemophilia in the United States. There are no national, regional or ethnic groups known to have increased incidence.
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Hemophilia


Hemophilia A is an X-linked, recessive, bleeding disorder caused by a
deficiency in the activity of coagulation factor VIII. Factor VIII (F8) is
the protein product of the HEMA gene, located at map position Xq28.
Affected individuals have internal bleeding in joints and muscles, easy
bruising, and prolonged bleeding from wounds. It affects
approximately 1 in 10,000 males in most populations (a similar
number of females are carriers). There are about 17,000 people
presently living with hemophilia in the United States. There are no
national, regional or ethnic groups known to have increased incidence.



Hemophilia A is caused by hundreds of different heterogeneous
mutations in the HEMA gene (base changes, insertions, deletions,
inversions). This gene seems to be a hotspot for mutation.
Approximately 1 out of 5 cases of hemophilia A is the result of a new
mutation, rather than a mutant gene inherited from the parents. The
disease shows a range of severity, which may be linked to the specific
type of mutation inherited and its effect on the function of the factor
VIII protein. Carrier detection and prenatal diagnosis can be done by
sequencing of the entire HEMA gene, or by detection of specific

mutations known to exist in a family. Therapy for the disease requires
replacement of factor VIII by injection of purified protein derived from
human plasma or recombinant techniques.

Question: Hemophilia A is famous as a disease of the Royal families of
Europe in the 19th and 20th centuries. Since hemophilia A is on the X
chromosome, was there an increased risk of having a child with
hemophilia in a consanguineous (same family) marriage?

Will a father with the disease produce children who have it?






This pedigree was created by Janet Stein Carter, Clermont College,
University of Cincinnati, who retains copyright.

Gene Therapy
Patients with Hemophilia A now receive regular injections of purified
factor VIII protein, which enables them to live nearly normal lives.
However, this therapy is expensive, and carries substantial lifelong
risks of infection since the protein is generally purified from donated
human blood, and must be injected by the patient. A much more
radical approach, that could lead to a permanent cure for the disease,
is gene therapy. Adding a new copy of the HEMA gene into the liver
cells of the patient

The current work on gene therapy uses a virus as a “vector” to carry
therapeutic genes into cells in the patient’s body. Adenovirus is often
chosen because it is non-lethal and can be easily manipulated using
biotechnology techniques. Adenovirus is efficient at infecting human
cells and can be grown in the laboratory.


Adenoviruses are non-enveloped viruses containing a linear double
stranded DNA genome. There are over 40 strains of adenovirus, most
of which cause benign respiratory tract infections in humans. The virus
does not normally integrate into the host genome, rather they
replicate as episomal elements in the nucleus of the host cell. As a
result, adenovirus is eliminated from the body of an infected person by
the immune system after a period of time, which may range from a
few days to a few months. After repeated exposure to adenovirus, a
person may develop enhanced immunity, which could prevent
repeated infection, or possibly lead to severe allergic reaction.





The wild type adenovirus genome is approximately 35 kb, of which up
to 30 kb can be replaced with foreign DNA. The most recent vectors
contain only the inverted terminal repeats (ITRs) and a packaging

sequence around the transgene, all of the necessary viral genes being
provided by a second “helper” virus.

A New Adenoviral Vector: Replacement of All Viral Coding Sequences with 28 kb of
DNA Independently Expressing both Full-Length Dystrophin and B-Galactosidase
S Kochanek, PR Clemens, K Mitani, H Chen, S Chan, and CT Caskey
Proc Natl Acad Sci U S A. 1996 June 11; 93(12): 5731–5736.
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=39129


Your Assignment:
Design a gene therapy vector that could be used to cure hemophilia A.

1) Locate the coding sequence of the human HEMA (F8) gene in an
online database of the human genome (UCSC Genome Browser)
2) Locate the sequence of an adenovirus that can be used for
human gene therapy
3) Design a cloning strategy using restriction enzymes and ligase
that would enable you to insert the HEMA gene into the
adenovirus vector.


1) Find the DNA (Nucleotide) sequence of the normal human HEMA
gene.

The easiest place to find a single standard sequence for the human
genome is the UCSC Genome Brower: http://genome.ucsc.edu/ (see
Genomes Tutorial).

Go to the Genome Browser home page and click on the link to
Genome Browser. Choose “human” from the genome pulldown
menu, and then type “HEMA” in the text box for position, then hit
the Submit button.



The HEMA gene shows up under the “Known Genes” heading. Click on
it to go to the chromosome map.







Questions:
What chromosome is the HEMA (F8) gene on?

How long is this gene?

How many exons and introns does it have?

The factor VIII protein is 2351 amino acids long. What makes the
sequence on the chromosome so much longer?



The adenovirus vector can only hold 30 kb (30,000 base pairs) of
inserted DNA, so we can’t use the full genomic segment in our
engineered gene therapy virus. We need to use the protein coding
parts of the gene (the exons) plus some of the upstream sequence
(the promoter) and some downstream sequence. Fortunately, the
Genome Browser makes it quite easy to get exactly the sequence that
is needed. On the RefSeq Gene page, scroll down to the “Links to
Sequence” section and click on the link for “Genomic Sequence from
assembly.”




Now there are a number of options to set up exactly what sequence
you want to retrieve from the database. Check the box for
“Promoter/Upstream by 1000 bases” and uncheck the box for
“Introns” (this will remove all introns from the sequence that is
retrieved). We also want to add 500 bases past the end of the gene,
so check the box for “Downstream by 100 bases.” Also, make sure
that under “Sequence Formatting Options,” the button is set to “Exons
in upper case, everything else in lower case.” Then hit the “submit
button. You will get a screen full of DNA sequence. Save this sequence
to a word processing file. Note that the first 1000 bases are in lower
case, then several thousand uppercase bases, and finally 1000 bases
in lowercase at the end. It is within these two lowercase sections that
you wish to find restriction enzyme recognition sites.






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