Pathophysiology of Blood Disorders, Second Edition by Bunn Howard Franklin & Aster Jon C

Author:Bunn, Howard Franklin & Aster, Jon C. [Bunn, Howard Franklin]
Language: eng
Format: azw3
Publisher: McGraw-Hill Education
Published: 2017-01-05T16:00:00+00:00

GENETICS

As might be surmised from the range of phenotypes, hemophilia A is a genetically heterogeneous disease. A wide variety of factor VIII gene mutations have been identified in hemophilia patients, including missense mutations, nonsense mutations leading to premature termination of translation, frame shifts, deletions, and rearrangements. The most commonly encountered mutation, depicted in Figure 15-2A, is an inversion that reverses the orientation of the 3′ end of the gene relative to the 5′ promoter and transcriptional start site. Alleles bearing this rearrangement, observed in about 50% of severe hemophilia A patients, make no factor VIII. As shown in Figure 15-2B, the great majority of mutations in patients with severe hemophilia A have either inversions, large deletions, nonsense mutations, or frame shifts, all of which preclude synthesis of full-length factor VIII. In contrast, those with moderate or mild hemophilia A usually have missense mutations in which full-length protein is produced but has impaired stability or function.

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