(4.6) MOLECULAR BIOLOGY AND GENETICS OF HUMAN DISEASE

Molecular Biology and Genetics of Human Disease Summary

• Overall Goal: Understand the relationship between molecular and genetic changes in human disease.
• Objectives:
  • Compare and contrast genetic mutations in germline vs. somatic cells.
  • Compare and contrast molecular and genetic predisposition in disease.
  • Define terms: gain of function, loss of function, proto-oncogene, oncogene, tumor suppressor gene, fusion genes/proteins, hyperplasia, dysplasia, anaplasia, benign, and malignant.
  • Evaluate the relationship between molecular biology and development/progression in specific diseases: Asthma/COPD (COX-2), Male Infertility (DAZ), Metabolic Syndrome (insulin signaling), Marfan Syndrome (TGF-β), Congenital Immunodeficiencies (BTK), and Neoplasms.
  • Explain the role of signaling pathways in each disease.
  • Identify consequences of changes in genes/proteins (gain/loss of function).
  • Identify specific molecular and genetic changes that correspond with diseases/conditions: Asthma/COPD (COX-2), Male Infertility (DAZ), Metabolic Syndrome (insulin signaling), Marfan Syndrome (TGF-β), X-linked Agammaglobulinemia (BTK), and Neoplasms.

Somatic vs. Germline

• Somatic:
  • Changes occur in non-reproductive cells throughout the organism's lifetime.
  • Changes are not passed to offspring.
  • Mitotic nondisjunction and rearrangements play a role.
• Germline:
  • Changes occur in reproductive cells (oocytes and spermatocytes).
  • Changes are inheritable and can be passed to offspring.
  • Meiotic nondisjunction plays a role (and also early mitotic events).

Molecular Biology vs. Genetics

• Molecular Biology:
  • Interactions/processes that promote or cause disease; may not be heritable.
  • Can include genetic changes, but more often involves biochemical properties or cellular behaviors.
  • Evaluation of relevant biochemical and cellular behaviors essential.
• Genetics:
  • Inherited changes that affect future generations.
  • Similar processes/genes are often involved as in molecular biology, but the initiating event (inherited mutation) has to occur in a germ cell.
  • Inherited changes = predisposition for developing a particular condition.

Molecular Biology of Human Disease

• Molecular Biology relevant to various diseases including: Respiratory Diseases, Reproductive Disorders, Metabolic Disorders, Circulatory Diseases, Neoplastic Diseases/Cancers, Opportunistic Infections, Musculoskeletal Disorders, Sexually Transmitted Diseases, and Neuropsychiatric Disorders.
• Many diseases are a mix of inherited predispositions and acquired changes in somatic cells.

Potential Changes: Terminology

• Gain of Function:
  • Increased transcription or activity in a molecule.
  • Often due to loss of regulation, may be a single event initiating disease.
• Loss of Function:
  • Reduced transcription or activity in a molecule.
  • Usually a regulatory function lost, contributing to disease progression.
  • Includes Protooncogenes vs Oncogenes & Tumor Suppressor Genes

Respiratory Diseases: Asthma and COPD

• Characterized by chronic inflammation of the respiratory system.
• Both conditions can involve environmental and genetic factors, particularly microRNAs.
• COX-2 plays a role in inflammation progression.
• Factors like cigarette smoke can increase COX-2 expression.

Inherited Mutations in COX-2

• Mutations in COX-2 can be linked to multi-system abnormalities, mitochondrial disorders, stroke risk, neurodegenerative disorders.
• COX-2 variations can be associated with cancer and poorer prognosis.
• Some variations are recessive (loss-of-function).

Connecting Back to Neurogenetics: Another implication for COX-2

• COX-2's role in normal synaptic activity/plasticity is implicated in brain diseases.
• COX-2 linked to signaling through NF-kB, thus increasing neuroinflammation.

Male Infertility

• Approximately 15% of couples experience infertility due to issues of male infertility.
• Microdeletions of key genes on the Y chromosome are a common cause (AZF region).
• Genes are involved in spermatogenesis (e.g., DAZ).
• Loss of function for these genes means a complete inability to generate viable sperm (azoospermia).

DAZ Activity in Spermatogenesis

• DAZ activity is crucial in regulating spermatogenesis (growth & maturation of germ cells).
• Mutations affecting the RNA-binding or tandem repeat domains disrupt the protein's function.

Molecular Biology of Metabolic Syndrome

• A combined occurrence of several risk factors (insulin resistance, obesity, hypertension, and dyslipidemia).
• Insulin resistance is a key factor, linked to receptor expression/down-regulation.
• Other factors like PI3K, IRS, and GLUT-4 alter receptor and downstream player activity.

Genetics of Metabolic Syndrome

• Multiple genes contribute to the risk of metabolic syndrome.
• Quantitative Trait Loci (QTLs) are associated with the syndrome.
• Candidate genes include: LDLR, TGF-β, IL-6, and SELE.

Molecular Biology of Cardiovascular Disease

• Reactive oxygen species (ROS) and signaling alterations are important in cardiovascular disease development.
• TGF-β signaling is associated with cardiomyocyte apoptosis, cardiac hypertrophy & myocardial infarctions.
• TGF-β's role in tissue response and repair is also pertinent.

Marfan Syndrome

• Rare, autosomal-dominant, multisystem disorder (skeletal, cardiovascular, & ocular).
• Inherited mutations in Fibrillin-1 (FBN1) alter TGF-β signaling pathways and thereby increase its activation (dysregulation).

Congenital Immunodeficiencies

• Rare but collectively affect approximately 1 in 10,000 people.
• Often include severe/unusual infections, autoimmune or autoinflammatory diseases, and/or predisposition to malignancies (e.g., X-linked Agammaglobulinemia).

X-linked Agammaglobulinemia (XLA)

• X-linked recessive disorder, predominantly affecting males.
• Pathogenic mutations in the BTK gene cause a B-cell intracellular tyrosine kinase deficiency.
• BTK is critical for pre-B cell maturation into mature B cells, leading to recurrent bacterial infections and a reduced immune response.

Neoplasms/Cancer

• Changes in key molecular production and behavior result in a range of neoplasms/cancer.
• Primarily somatic changes result in sporadic cancer; some predispositions are inherited.
• Understanding both molecular biology and genetics of cancer is crucial for comprehension.

The Hallmarks of Cancer

• Molecular processes of cancer development and progression, as summarized by Hannahan and Weinberg.
• Emerging characteristics and updated hallmarks of cancer cells.
• Somatic mutation theory and tissue organization field theory comparisons/contrasts.
• Assessment of consequences for changes in molecular characteristics (based on hallmarks and discussed genes).

Check-in Questions

• Questions focus on understanding the reasons behind infertility and the signaling pathways related to cardiovascular diseases.

Linking Gene Changes to Hallmarks

• Determining which hallmarks are the initiating event of neoplasms.
• Assessing the role of chromosome level changes in influencing hallmark activity.

Additional topics not broken into subtitles:

• Presented data for various conditions (e.g Asthma/COPD, Male Infertility, Metabolic Syndrome, Marfan Syndrome, Congenital Immunodeficiencies, and Neoplasms).
• Data in tables/figures were referenced as needed.
• Information on the relationship between disease, mechanisms and potential targeted therapy.

This quiz covers the relationship between molecular and genetic changes in human diseases. It compares genetic mutations in germline and somatic cells, as well as explores various diseases and their genetic implications, such as asthma, male infertility, and metabolic syndrome. Test your knowledge on key terms and concepts essential for a deeper understanding of molecular biology in the context of human disease.