Genetic and molecular bases of deseases

A.Y. 2018/2019
Lesson for
14
Max ECTS
111
Overall hours
SSD
BIO/13 MED/03
Language
English
Learning objectives
Relevant objectives of the first part of the course are to provide content concerning the organization of the human genome and the genetic and epigenetics mechanisms involved in genome mutation and in control of gene expression. The molecular mechanisms learned in the first part of the course will help to understand the regulation of specific function of the immune system and the pathogenesis of the immune diseases with perspective of gene therapy, as well as the pathogenetic basis of genetic diseases and cancer, topics covered in the second part of the course.
Acquiring competence on molecular mechanisms regulating genome plasticity and activity will allow to achieve the comprehension of molecular mechanisms underlying both constitutional monogenic and polygenic diseases, and cancer. Furthermore, experimental activities in labs, will give suitable skills to learn the current methods applied in molecular diagnosis of genetic diseases.

Course structure and Syllabus

Active edition
Yes
Responsible
Biology
BIO/13 - EXPERIMENTAL BIOLOGY - University credits: 8
Practicals: 24 hours
Lessons: 46 hours
Human genetics
MED/03 - MEDICAL GENETICS - University credits: 6
Lessons: 42 hours
Biology
Syllabus
ORGANIZATION OF THE HUMAN GENOME
1. Human multigene families
2. Extragenic conserved sequences
3. Extragenic and coding repeated DNA sequences
4. The coding genome
GENOME INSTABILITY
1. Mutations and polymorphisms of DNA
2. Genetic mechanisms underlying mutation of repeated sequences
3. Segmental duplications, CNVs and the causative molecular mechanisms
MOLECULAR PATHOGENETIC MECHANISMS
1. Classification and database nomenclature of mutations
2. Loss and gain of function mutations
3. Pathogenic potential of repeated sequences
4. The chromothripsis
5. The variable expressivity and the expression variability: the Noonan syndrome as model disease

MOLECULAR MECHANISM OF EPIGENETICS
1. An introduction to epigenetics
2. Role of Epigenetics in development and cell differentiation
3. Examples of different epigenetically-regulated phenomenon
4. Molecular mechanism of epigenetics: Covalent Histone modifications, ATP-dependent chromatin remodeling, histone variants.
EPIGENETIC TECHNOLOGIES
1. Functional characterization of regulatory DNA elements (promoters, enhancers, silencers, insulators)
2. Methods to study DNA-protein interactions in vitro.
3. Chromatin immunoprecipitation and in vivo applications.
EPIGENETICS AND HUMAN PATHOLOGIES
1. Epigenetics and neurodegenerative disease and neuropsychiatric disorders
2. Epigenetics and memory
3. Epigenetics and cancer
EPIGENETIC THERAPY

MEMORY IN THE INNATE AND ADAPTIVE IMMUNE SYSTEM
1. Epigenetics of the innate immune response: cell differentiation, stimulation and memory. Selectivity of the transcriptional response to stimulus.
2. Contribution of chromatin to cell memory.
3. Cells of the adaptive immune system.
4. Epigenetics of cell identity in the adaptive immune system.
ROLE OF AIRE IN THE PHYSIOLOGY AND PATHOPHYSIOLOGY OF THE IMMUNE system
1. The thymus as lymphopoietic organ.
2. T cell physiology. "Autoimmune regulator" (AIRE) in the regulation of ectopic tissue antigens expression in the thymus. The APECED syndrome ("Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy") by mutations of AIRE.
PRIMARY IMMUNODEFICIENCIES
1. Classification of primary immunodeficiencies.
2. Immunodeficiencies with dysregulation of the immune response.
3. Immunodeficiencies with impaired cell-mediated cytotoxicity.
4. Defects in the innate immune system.
INDUCED PLURIPOTENT STEM CELLS AS CELLULAR MODEL FOR THE STUDY OF DISEASES
1. Factors inducing stem cell pluripotency.
2. Examples of disease studied using induced pluripotent stem cells.
GENE THERAPY
1. Principles of gene therapy.
2. Vectors for gene therapy. Retroviral, lentiviral, adenoviral vectors; vectors based on adeno-associated and herpes simplex virus.
3. Disorders approached by gene therapy.
4. Possible complications of gene therapy.
POSSIBLE FUTURE OF GENE THERAPY
Human genetics
Syllabus
MONOGENIC DISEAS
1. Correlated pathologies to the gene CFTR: how does it occur?
2. GENOMIC DISORDERS
3. Recurrent and non-recurrent genomic rearrangements and disease traits
a. CMT1A
b. Smith-Magenis Syndrome
c. Chromosome 22q11.2 rearrangement disorders
4. Cryptic inversion mediates genomic disorders: examples in human diseases (Sotos syndrome, Williams syndrome, 17q21.31 microdeletion syndrome)

MOSAICISM IN HUMAN DISEASES: FROM CNVS TO SNVS

PENETRANCE DEFECTS AND PHENOTYPE VARIABILITY: TOWARDS AN UNDERSTANDING OF THE MOLECULAR BASIS
1. TAR syndrome and the two hits condition
2. Marfan syndrome
3. Hemochromatosis

POSITION EFFECT MECHANISMS

CILIOPATHIES: FROM COMMON TO RARE DISEASES
1. Polycystic kidney disease: a first example of the growing list of disorders named "Ciliopathies"
2. Bardet-Biedl syndrome: a model for genetic interaction
LAMINOPATHIES: PRELAMIN A GENE A SINGLE GENE FOR SEVERAL DISEASES
CANCER GENETICS
1. Sporadic and inherited cancer predisposition
2. Colon cancer predisposition syndromes
3. Ovarian and breast cancer predisposition
4. Li-Fraumeni syndrome
5. MEN syndromes
6. Renal cancer predisposition
7. Druggable somatic alteration in cancers

GENETICS OF DIABETES
1. From monogenic to "common" type 2 diabetes
2. Fetal programming and adult health
3. Nutrigenetics and nutrigenomics

REPRODUCTIVE GENETICS AND GENOMICS
1. Genetic mechanisms in DSD (disorder of sex development)
2. Epigenetic reprogramming in the germline and early embryo
3. Chromosomal instability in pre-implantation embryo.

MITOCHONDRIAL DYSFUNCTIONS
1. Mitochondrial disorders caused by defects of nuclear DNA
2. Mitochondrial disorders caused by defects of mtDNA
3. Mitochondrial dysfunctions in cancer.

GENOMIC IMPRINTING AND RELATED SYNDROMES
1. 11p15.5 related syndromes (Beckwith-Wiedemann, Silver Russell syndrome, IMAGE)
2. Multilocus Imprinting Disorders
3. The 15q11.2-13 imprinted region and related syndromes (Prader-Willi and Angelman syndromes)
Lesson period
Second trimester
Lesson period
Second trimester
Assessment methods
Esame
Assessment result
voto verbalizzato in trentesimi
Professor(s)
Reception:
Appointment upon request
Dept. Medical Biotechnology and Translational Medicine, Via F.lli Cervi 93, 20090 Segrate