Relationship between Genotype and Phenotype in Genetic Disease

 Allelic heterogeneityThe occurrence of more than one allele at a locusα-Thalassemia
β-Thalassemia Locus heterogeneityThe association of more than one locus with a clinical phenotypeThalassemia can result from mutations in either the α-globin or β-globin genesClinical or phenotypic heterogeneityThe association of more than one phenotype with mutations at a single locusSickle cell disease and β-thalassemia each result from distinct β-globin gene mutations

Allelic Heterogeneity

A second explanation for allele-based variation in phenotype is that the variation may reflect the specific property of the protein that is most perturbed by the mutation. This situation is well illustrated by Hb Kempsey, a β-globin allele that maintains the hemoglobin in a high oxygen affinity structure, causing polycythemia because the reduced peripheral delivery of oxygen is misinterpreted by the hematopoietic system as being due to an inadequate production of red blood cells.

The biochemical and clinical consequences of a specific mutation in a protein are often unpredictable. Thus no one would have foreseen that the β-globin allele associated with sickle cell disease would lead to the formation of globin polymers that deform erythrocytes to a sickle cell shape (see later in this chapter). Sickle cell disease is highly unusual in that it results only from a single specific mutation—the Glu6Val substitution in the β-globin chain—whereas most disease phenotypes can arise from any of a number or many substitutions, usually loss-of-function mutations, in the affected protein.

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Nov 27, 2016 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on Relationship between Genotype and Phenotype in Genetic Disease

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