Hemophilia A
From Iusmgenetics
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===Mode of inheritance=== | ===Mode of inheritance=== | ||
*'''X-linked recessive''' | *'''X-linked recessive''' | ||
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===Single important gene=== | ===Single important gene=== | ||
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===Etiology=== | ===Etiology=== | ||
*There are a variety of mutations and mutation types (large / small deletions, insertions, missense, etc.) that cause hemophilia A. | *There are a variety of mutations and mutation types (large / small deletions, insertions, missense, etc.) that cause hemophilia A. | ||
| + | **Large or small deletions, insertions, missense, etc. | ||
**We will use Hemophilia A specifically as '''an example of unusual crossing over'''. | **We will use Hemophilia A specifically as '''an example of unusual crossing over'''. | ||
***Occurs in 40-50% of Hemophilia A cases | ***Occurs in 40-50% of Hemophilia A cases | ||
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*Unusual crossing over: | *Unusual crossing over: | ||
| - | **In hemophilia A, an inversion within the gene | + | **In hemophilia A, an inversion within the gene allows for crossing over that causes disruption of the gene. |
**'''The inversion in Hemophilia A usually occurs during male meiosis'''. | **'''The inversion in Hemophilia A usually occurs during male meiosis'''. | ||
**Recall that exons are numbered for their position (starting with 1) as one moves in the direction of transcription. | **Recall that exons are numbered for their position (starting with 1) as one moves in the direction of transcription. | ||
Current revision as of 19:17, 13 December 2011
Contents |
[edit] Hemophilia A
[edit] General background information
[edit] Mode of inheritance
- X-linked recessive
[edit] Single important gene
- The FVIII gene makes the clotting cascade enzyme Factor VIII.
- The gene is large: 186 kb with 26 exons.
[edit] Etiology
- There are a variety of mutations and mutation types (large / small deletions, insertions, missense, etc.) that cause hemophilia A.
- Large or small deletions, insertions, missense, etc.
- We will use Hemophilia A specifically as an example of unusual crossing over.
- Occurs in 40-50% of Hemophilia A cases
- Unusual crossing over:
- In hemophilia A, an inversion within the gene allows for crossing over that causes disruption of the gene.
- The inversion in Hemophilia A usually occurs during male meiosis.
- Recall that exons are numbered for their position (starting with 1) as one moves in the direction of transcription.
- The wild-type order is 1->26.
- There are, however, inverted repeats downstream of the first exon and upstream of the 22nd exon that can pair to allow inversion.
- The inversion flips exons 1-22 over, leaving the final order 22->...->1->23->...->26
[edit] Pathogenesis
- Pts with > 25% function of factor VIII of the clotting cascade will have no symptoms.
- As the amount of factor VIII function approaches 5% of normal, symptoms begin to manifest.
- < 1% factor VIII function manifests severe disease: frequent bleeding (even spontaneously), bleeding into joints
[edit] Phenotypic information
- External bleeding episodes
- Prolonged bleeding from a circumcision wound or a venepuncture or heelprick is another common early sign of haemophilia
- Prolonged bleeding from common injuries, or in severe cases bleeds may be spontaneous and without obvious cause.
- The most serious sites of bleeding are: joints, muscles, digestive tract, and brain
- The muscle and joint haemorrhages are indicative of haemophilia
- Digestive tract and cerebral haemorrhages are also germane to other coagulation disorders
- Repeated bleeds into a joint capsule can cause permanent joint damage and disfigurement resulting in chronic arthritis and disability.
- Joint damage is not a result of blood in the capsule but rather the healing process.
- When blood in the joint is broken down by enzymes in the body, the bone in that area is also degraded.
