There are different mechanisms through which chromosomal position effect (CPE) can result in developing human abnormalities: juxtaposition of one gene with the enhancer of another gene, separation of the transcription unit from an essential distant regulatory element, competition for the same regulatory element, or classical PEV where a gene is transferred to a new chromatin environment. Pathogenesis associated with CPE can be found in various cancers, or constitutional pathologies, in which chromosomal rearrangements (translocations, deletions, or inversions) take place (1).
A) Burkitt’s lymphoma t(8;14)(q24;q32) can be developed due to chromosomal translocations juxtaposing the c-myc gene on chromosome 8 to one of the immunoglobulin loci. This aggressive B-cell neoplasm is characterized by c-MYC gene placed near the enhancer of the heavy chain of immunoglobulin on chromosome 14, which results in overexpression of c-MYC in B cells. This type of lymphoma makes up the majority of BL (2).B) Alpha-thalassemia is an inherited blood disorder that is characterized by reduced production of hemoglobin. This pathology can be seen in individuals whose level of alpha-globin chain composing hemoglobin is decreased.
Alpha-globin protein is expressed from four genes (HBA1 and HBA2 on each chromosome 16) that are under the control of a 5? regulatory element, 5?-HS40. Typically, alpha-thalassemia develops when the deletion of either the alpha-globin genes or the 5? regulatory element occurs (3).C) Progeria (Hutchinson-Gilford Progeria Syndrome or “HGPS”) is characterized by extremely rapid, premature aging of newborns shortly after their birth.
Individuals with HGPS have point mutations in the Lmna encoding lamin A and C, the A-type lamins – crucial structural element of the nuclear envelope. The most frequent HGPS mutation is located at codon 608 (G608G). This type of mutation forms a cryptic splice site within exon 11 deleting a proteolytic cleavage site within the expressed mutant lamin A. This leads to incomplete processing of prelamin A resulting in nuclear lamina abnormalities common for HGPS cells (4).