Chromosome 14 Robert Rella - PowerPoint PPT Presentation

Chromosome 14 Robert Rella https://public.ornl.gov/site/gallery/detail.cfm?id=344

Overview Nuts and bolts u Genes u Translocations u Multiple Myeloma u PSEN1 and TRA – noteworthy genes u Unique features of chromosome 14 u 3xTg-AD Alzheimer’s Mouse Model u Annotated bibliography u

Nuts and bolts ⎈ Genes ⎈ Translocations ⎈ Multiple Myeloma ⎈ PSEN1 and TRA ⎈ Unique features ⎈ 3xTg-AD ⎈ Resources Nuts and Bolts One of six acrocentric u chromosomes – susceptible to Robertsonian translocations 87,410,661 bp heterochromatin u 107,043,718 bp total u Longest: 248,956,422 bp u MT = Mitochondrial DNA Shortest: 46,709,983 bp https://commons.wikimedia.org/wiki/File:Ideogram_human_chromosome_14.svg u 3 regions on q arm u 1 region on p arm u

Nuts and bolts ⎈ Genes ⎈ Translocations ⎈ Multiple Myeloma ⎈ PSEN1 and TRA ⎈ Unique features ⎈ 3xTg-AD ⎈ Resources Genes Genes Genes 60 disease genes 60 disease genes u u 60 disease genes u 1,050 genes and gene fragments 1,050 genes and gene fragments u u 1,050 genes and gene fragments u 393 pseudogenes 393 pseudogenes u u 393 pseudogenes u The p arm consists of almost entirely rRNA genes The p arm consists of almost entirely rRNA genes u u The p arm consists of almost entirely rRNA genes u https://ghr.nlm.nih.gov/chromosome/14#idiogram

Nuts and bolts ⎈ Genes ⎈ Translocations ⎈ Multiple Myeloma ⎈ PSEN1 and TRA ⎈ Unique features ⎈ 3xTg-AD ⎈ Resources Robertsonian Translocation https://ib.bioninja.com.au/standard-level/topic-3-genetics/32-chromosomes/chromosome-types.html https://www.medschool.lsuhsc.edu/genetics/down_syndrome.aspx https://www.khanacademy.org/test-prep/mcat/biological-sciences-practice/biological-sciences-practice-tut/e/translocations-in-the-germline u Chromosome 14 is most famous for its involvement in Familial Down Syndrome, where a Robertsonian translocation occurs between chromosomes 14 and 21, which causes trisomy 21. Robertsonian u A Robertsonian translocation (ROB) is the fusion of the q arms of any of the acrocentric chromosomes, generating a massive chromosome and a small fragment, which is Translocations often lost. u Acrocentric is defined as having the centromere situated so that one chromosomal arm is much shorter than the other u The acrocentric chromosomes are 13, 14, 15, 21, 22, and y

Nuts and bolts ⎈ Genes ⎈ Translocations ⎈ Multiple Myeloma ⎈ PSEN1 and TRA ⎈ Unique features ⎈ 3xTg-AD ⎈ Resources Multiple Myeloma Multiple Myeloma (MM) is a very u malignant disorder associated with chromosome 14. MM is characterized by the u uncontrolled proliferation of clonal plasma cells. Wide variety of complications u leading to organ dysfunction and eventually death. https://emedicine.medscape.com/article/204369-overview

Nuts and bolts ⎈ Genes ⎈ Translocations ⎈ Multiple Myeloma ⎈ PSEN1 and TRA ⎈ Unique features ⎈ 3xTg-AD ⎈ Resources Multiple Myeloma: causes and effects Cytogenetic abnormalities induce MM u by causing plasma cells to proliferate uncontrollably, escape apoptosis, and https://www.mayoclinic.org/ diseases-conditions/multiple- evade the immune system. myeloma/symptoms- causes/syc- 20353378?utm_source=Google &utm_medium=abstract&utm _content=Multiple- Translocation of oncogenes to u myeloma&utm_campaign=Kno wledge-panel chromosome 14, specifically to the immunoglobulin heavy chain gene. Malignant cells produce irregular u monoclonal antibodies. Upon clonal expansion of malignant u plasma cells, they replace natural bone marrow, leading to anemia, other cytopenias, and lytic bone lesions. Impairment of the bone marrow u compromises the immune system, leading to immunoparesis and recurrent infections. https://www.vectorstock.com/royalty-free-vector/multiple-myeloma-diagram-vector-16434816

Nuts and bolts ⎈ Genes ⎈ Translocations ⎈ Multiple Myeloma ⎈ PSEN1 and TRA ⎈ Unique features ⎈ 3xTg-AD ⎈ Resources PSEN1 and TRA PSEN1 is orange PSEN1 is a noteworthy gene on TRA is a noteworthy gene on u u chromosome 14 chromosome 14 Presenilin 1 (PSEN1) T cell Receptor Alpha (TRA) u u TRA pairs with TRB on ⍺ / β T cells to Presenilin 1 is the proteolytic subunit u u of 𝛿 -secretase form the T cell receptor https://en.wikipedia.org/wiki/Gamma_secretase 𝛿 -secretase is a multimeric In humans, the T cell receptor is how u u transmembrane enzyme that cleaves T cells recognize molecules single pass transmembrane proteins, presented by antigen presenting cells the most notable of which is β - on HLA complexes amyloid precursor protein (APP) Mutations in PSEN1 are causative of u Familial early-onset Alzheimer’s Disease http://pathobiologyresearch.com/keller/index.php/diagnostics/clonality/principles/

Nuts and bolts ⎈ Genes ⎈ Translocations ⎈ Multiple Myeloma ⎈ PSEN1 and TRA ⎈ Unique features ⎈ 3xTg-AD ⎈ Resources PSEN1 PSEN1 is the proteolytic subunit One of the most characteristic u pathologies of Alzheimer’s Disease is the deposition of senile plaques in the brain formed by the accumulation of extracellular b -amyloid peptides. b -amyloid is generated from the b - u amyloid precursor protein (APP) following cleavage by the b - and g - secretase enzymes. 𝛿 -secretase is currently an appealing u therapeutic target for AD treatment. Normal functioning 𝛿 -secretase acts u to cleave a plethora of transmembrane proteins, including the cell fate-determining protein Notch. Ablation (knockout of all four u subunits) of 𝛿 -secretase results in embryonic fatality, proving that 𝛿 - secretase is necessary for survival.

Nuts and bolts ⎈ Genes ⎈ Translocations ⎈ Multiple Myeloma ⎈ PSEN1 and TRA ⎈ Unique features ⎈ 3xTg-AD ⎈ Resources TRA https://www.bio-rad-antibodies.com/t-cell-receptor-minireview.html The TCR is how the immune system can respond to a potentially infinite u number of possible antigens with a finite genome https://en.wikipedia.org/wiki/T-cell_receptor Two major subsets of TCRs expressed by T cells: ⍺ / β and 𝛿 / 𝜀 u a / b T cells express a TCR heterodimer composed of both an alpha chain and a u beta chain. The alpha chain is derived from the TRA gene on chromosome 14. This subset of T cells can be found readily throughout the systemic circulation u and lymphoid organs. a / b T cells bind to Human Leukocyte Antigen (HLA) complexes that act as a molecular cradle for an antigen. These cells preferably bind peptide antigens, although it has been shown that https://www.rcsb.org/3d-view/4UDT/1 u a / b T cells are also capable of binding lipid antigens in the analogous CD1 protein complex.

Nuts and bolts ⎈ Genes ⎈ Translocations ⎈ Multiple Myeloma ⎈ PSEN1 and TRA ⎈ Unique features ⎈ 3xTg-AD ⎈ Resources Unique Features Ring 14 Syndrome u u Under unique circumstances, chromosome 14 can form a ring shape. u This is due to small breaks in both arms leading to fusion of the p and q terminals https://ghr.nlm.nih.gov/condition/ring-chromosome-14-syndrome u Ring chromosome 14 syndrome is a condition characterized by drug-resistant seizures and intellectual disability. u Interestingly, the researchers found that no DNA is lost in about 20% of cases, implying a spontaneous fusion of the p and q arms. Terminal deletion 14 syndrome u u Chromosome 14q deletion is a chromosome abnormality that occurs when there is a missing copy of genetic material on the q arm of chromosome 14 u Symptoms often include developmental delay, intellectual disability, behavioral problems and distinctive facial features u Most of the time, this syndrome arises de novo https://en.wikipedia.org/wiki/Deletion_(genetics)

Nuts and bolts ⎈ Genes ⎈ Translocations ⎈ Multiple Myeloma ⎈ PSEN1 and TRA ⎈ Unique features ⎈ 3xTg-AD ⎈ Resources Triple Transgenic AD Mouse https://www.jax.org/strain/004807 The 3x Tg-AD mouse is an animal model for Alzheimer’s Disease. u 3x = Triple u Tg = Transgenic (defined as an organism that contains genetic material into u which DNA from an unrelated organism has been artificially introduced) AD = Alzheimer’s Disease u The 3x Tg-AD mouse has 3 transgenes that affect female mice more strongly, u so usually females are used for research purposes. The transgenes are a mutated PSEN1, an overexpressing APP gene, and a gene u that causes the hyperphosphorylation of Tau protein (which subsequently leads to the formation of neurofibrillary tangles) https://mus.brc.riken.jp/en/mouse_of_month/sep_2014_mm