Genetic Disorders of the HL System

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-Hematopoesis is known to be guided by more than 20 genes. There are a bunch of mutations that create impairment because of this. Certain mutations will arrest differentiation in different stages and you won’t have an effective population of certain cells to carry out a specific function. This commonly leads to lethality of the cell line since critical cells are not produced.

-Significant subset of genes relative to hematopoesis and to functioning of the differentiated cells are a set of growth factors and their receptors. They function to regulate replication of the hematopoetic cells and transcription of these genes. There are two broad categories of these receptors/growth factors

-tyrosine kinase activity receptors- membrane bound, the cytoplasmic domain has tyrosine kinase activity, which will phosphorylate other molecules, this will trigger an intracellular cascade of phosphorylations. The external domain includes a series of immunoglobulin like domains (100 amino-acids in length, two cysteines in each domain, there is sulfur-sulfur reduction between the two domains to bring about a certain confirmation.)

-cytokine super family: example erythropoietin it is a grow factor that stimulates the differentiations of erythopoietic cells. There can be certain mutations in the receptor for erythropoietin. These mutations represent, Intra Locus Genetic Heterogeneity, and phenotype heterogeneity.

There are a couple of mutations in the locus that make for impairment of erythropoiesis and some that stimulate it. 4 examples of these mutations are:
-extracellular motif in the receptor that is highly conserved sequence. Mutations in it have the consequence that they bring about sequestration of the receptor when it is taken into the cell. So, that it cannot function as a transmission signal

-mutation in the cytoplasmic domain of the receptor called a truncating mutation, a segment is blocked off by the mutation. There will be no transmission of signal when erythropoietin binds.

-there is a arginine at position 129 in the receptor, if you substitute for the arginine, with cysteine this will bring a dimerization between two receptors and this will make the receptor independent. It will keep signaling in the absence of erythopoetin

-there is a truncating mutation in the cytoplasmic domain of the receptor which will bring an abnormal signaling so that you have an excessive erythrocytosis (increased numbers of RBC). 70 amino acids are truncated

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Category: Biology , Cellular differentiation , Cytokine , Featured , Gene , Growth factor , Medical Subject Notes , Mutation , Phosphorylation , Tyrosine kinase