Chromosome 14 Robert Rella - - PowerPoint PPT Presentation

Chromosome 14

Robert Rella

Overview

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Nuts and bolts

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Genes

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Translocations

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Multiple Myeloma

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PSEN1 and TRA – noteworthy genes

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Unique features of chromosome 14

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3xTg-AD Alzheimer’s Mouse Model

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Annotated bibliography

Nuts and Bolts

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One of six acrocentric chromosomes – susceptible to Robertsonian translocations

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87,410,661 bp heterochromatin

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107,043,718 bp total

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Longest: 248,956,422 bp

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Shortest: 46,709,983 bp

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3 regions on q arm

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1 region on p arm

MT = Mitochondrial DNA

https://commons.wikimedia.org/wiki/File:Ideogram_human_chromosome_14.svg

Nuts and bolts ⎈ Genes ⎈ Translocations ⎈ Multiple Myeloma ⎈ PSEN1 and TRA ⎈ Unique features ⎈ 3xTg-AD ⎈ Resources

Genes

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60 disease genes

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1,050 genes and gene fragments

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393 pseudogenes

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The p arm consists of almost entirely rRNA genes

Genes

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60 disease genes

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1,050 genes and gene fragments

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393 pseudogenes

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The p arm consists of almost entirely rRNA genes

Genes

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60 disease genes

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1,050 genes and gene fragments

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393 pseudogenes

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The p arm consists of almost entirely rRNA genes

https://ghr.nlm.nih.gov/chromosome/14#idiogram

Nuts and bolts ⎈ Genes ⎈ Translocations ⎈ Multiple Myeloma ⎈ PSEN1 and TRA ⎈ Unique features ⎈ 3xTg-AD ⎈ Resources

Robertsonian Translocations

uChromosome 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.

uA 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

• ften lost.

uAcrocentric is defined as having the centromere situated so that one chromosomal arm is

much shorter than the other

uThe acrocentric chromosomes are 13, 14, 15, 21, 22, and y

Robertsonian Translocation

https://www.medschool.lsuhsc.edu/genetics/down_syndrome.aspx

Nuts and bolts ⎈ Genes ⎈ Translocations ⎈ Multiple Myeloma ⎈ PSEN1 and TRA ⎈ Unique features ⎈ 3xTg-AD ⎈ Resources

Multiple Myeloma

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Multiple Myeloma (MM) is a very malignant disorder associated with chromosome 14.

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MM is characterized by the uncontrolled proliferation of clonal plasma cells.

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Wide variety of complications leading to organ dysfunction and eventually death.

Nuts and bolts ⎈ Genes ⎈ Translocations ⎈ Multiple Myeloma ⎈ PSEN1 and TRA ⎈ Unique features ⎈ 3xTg-AD ⎈ Resources

https://emedicine.medscape.com/article/204369-overview

Multiple Myeloma: causes and effects

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Cytogenetic abnormalities induce MM by causing plasma cells to proliferate uncontrollably, escape apoptosis, and evade the immune system.

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Translocation of oncogenes to chromosome 14, specifically to the immunoglobulin heavy chain gene.

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Malignant cells produce irregular monoclonal antibodies.

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Upon clonal expansion of malignant plasma cells, they replace natural bone marrow, leading to anemia,

• ther cytopenias, and lytic bone

lesions.

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Impairment of the bone marrow compromises the immune system, leading to immunoparesis and recurrent infections.

Nuts and bolts ⎈ Genes ⎈ Translocations ⎈ Multiple Myeloma ⎈ PSEN1 and TRA ⎈ Unique features ⎈ 3xTg-AD ⎈ Resources

PSEN1 and TRA

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PSEN1 is a noteworthy gene on chromosome 14

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Presenilin 1 (PSEN1)

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Presenilin 1 is the proteolytic subunit

• f 𝛿-secretase

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𝛿-secretase is a multimeric transmembrane enzyme that cleaves single pass transmembrane proteins, the most notable of which is β- amyloid precursor protein (APP)

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Mutations in PSEN1 are causative of Familial early-onset Alzheimer’s Disease

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TRA is a noteworthy gene on chromosome 14

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T cell Receptor Alpha (TRA)

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TRA pairs with TRB on ⍺/β T cells to form the T cell receptor

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In humans, the T cell receptor is how T cells recognize molecules presented by antigen presenting cells

• n HLA complexes

Nuts and bolts ⎈ Genes ⎈ Translocations ⎈ Multiple Myeloma ⎈ PSEN1 and TRA ⎈ Unique features ⎈ 3xTg-AD ⎈ Resources

PSEN1 is orange

PSEN1

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One of the most characteristic pathologies of Alzheimer’s Disease is the deposition of senile plaques in the brain formed by the accumulation

• f extracellular b-amyloid peptides.

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b-amyloid is generated from the b- amyloid precursor protein (APP) following cleavage by the b- and g- secretase enzymes.

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𝛿-secretase is currently an appealing therapeutic target for AD treatment.

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Normal functioning 𝛿-secretase acts to cleave a plethora of transmembrane proteins, including the cell fate-determining protein Notch.

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Ablation (knockout of all four 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

PSEN1 is the proteolytic subunit

TRA

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The TCR is how the immune system can respond to a potentially infinite number of possible antigens with a finite genome

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Two major subsets of TCRs expressed by T cells: ⍺/β and 𝛿/𝜀

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a/b T cells express a TCR heterodimer composed of both an alpha chain and a beta chain. The alpha chain is derived from the TRA gene on chromosome 14.

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This subset of T cells can be found readily throughout the systemic circulation and lymphoid organs. a/b T cells bind to Human Leukocyte Antigen (HLA) complexes that act as a molecular cradle for an antigen.

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These cells preferably bind peptide antigens, although it has been shown that 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

https://www.rcsb.org/3d-view/4UDT/1

Unique Features

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Ring 14 Syndrome

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 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.

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Terminal deletion 14 syndrome

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

Nuts and bolts ⎈ Genes ⎈ Translocations ⎈ Multiple Myeloma ⎈ PSEN1 and TRA ⎈ Unique features ⎈ 3xTg-AD ⎈ Resources

Triple Transgenic AD Mouse

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The 3x Tg-AD mouse is an animal model for Alzheimer’s Disease.

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3x = Triple

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Tg = Transgenic (defined as an organism that contains genetic material into which DNA from an unrelated organism has been artificially introduced)

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AD = Alzheimer’s Disease

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The 3x Tg-AD mouse has 3 transgenes that affect female mice more strongly, so usually females are used for research purposes.

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The transgenes are a mutated PSEN1, an overexpressing APP gene, and a gene that causes the hyperphosphorylation of Tau protein (which subsequently leads to the formation of neurofibrillary tangles)

Nuts and bolts ⎈ Genes ⎈ Translocations ⎈ Multiple Myeloma ⎈ PSEN1 and TRA ⎈ Unique features ⎈ 3xTg-AD ⎈ Resources

https://www.jax.org/strain/004807

Animal Study

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Triple-transgenic AD (3xTg-AD) and control mice at six months in age (24 weeks) were treated with AU-9 (5mg/kg) and Pioglitazone (14 mg/kg) for 1 month.

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• 1. Open Field & Novel Object Location Test:
• Day 1 & 2: habituation (10 min)
• Day 3: familiarization (4 min)
• Day 4: test (4 min)

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• 2. Y-maze:
• Training session-Novel arm closed
• Testing session- All 3 arms open

Animal Study

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Triple-transgenic AD (3xTg-AD) and control mice at six months in age (24 weeks) were treated with AU-9 (5mg/kg) and Pioglitazone (14 mg/kg) for 1 month.

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• 1. Open Field & Novel Object Location Test:
• Day 1 & 2: habituation (10 min)
• Day 3: familiarization (4 min)
• Day 4: test (4 min)

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• 2. Y-maze:
• Training session-Novel arm closed
• Testing session- All 3 arms open

Open Field & Novel Object Location Y maze

Nuts and bolts ⎈ Genes ⎈ Translocations ⎈ Multiple Myeloma ⎈ PSEN1 and TRA ⎈ Unique features ⎈ 3xTg-AD ⎈ Resources

Treatment groups:

Control mice Control mice + Pio Control mice + AU9 3x Tg-AD mice 3x Tg-AD mice + Pio 3x Tg-AD mice + AU9

Resources

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Al-Farsi, Khalil. 2013. Multiple myeloma: an update. Oman Medical Journal. 28 (1): 3-11.

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Attaf, M., Legut, M., Cole, D. K., Sewell, A. K. 2015. The T cell antigen receptor: the Swiss army knife of the immune system. Clinical and Experimental Immunology. 181 (1): 1–18.

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Heilig et al. 2003. The DNA sequence and analysis of human chromosome 14. Nature. 421: 601-607.

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Oddo S., Caccamo A., Shepherd J. D., et al. 2003. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 39 (3): 409–421.

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Petersen, M.B., Adelsberger, P .A., Schinzel, A.A., Binkert, F ., Hinkel, G.K., Antonarakis, S.E. 1991. Down syndrome due to de novo Robertsonian translocation t(14q;21q): DNA polymorphism analysis suggests that the origin of the extra 21q is maternal. American Journal of Human Genetics. 49 (3): 529-536.

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van Karnebeek, C. D., Quik, S., Sluijter, S., Hulsbeek, M. M., Hoovers, J. M., & Hennekam, R. C. 2002. Further delineation of the chromosome 14q terminal deletion syndrome. American Journal of Medical

• Genetics. 110 (1): 65-72.

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Zhang, X., Li Y ., Xu, H., & Zhang Y . W. 2014. The g-secretase complex: from structure to function. Frontiers in Cellular Neuroscience. 8: 1-10.

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Zollino, M., Ponzi, E., Gobbi, G., Neri G. 2012. The ring 14 syndrome. European Journal of Medical

• Genetics. 55 (5): 374-380.

Nuts and bolts ⎈ Genes ⎈ Translocations ⎈ Multiple Myeloma ⎈ PSEN1 and TRA ⎈ Unique features ⎈ 3xTg-AD ⎈ Resources