Genetic and molecular bases of diseases

A.Y. 2019/2020
14
Max ECTS
111.5
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.
Expected learning outcomes
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 syllabus and organization

Single session

Responsible
Lesson period
Second trimester
Prerequisites for admission
Mendelian genetics, basic knowledge of human genome structure.
Basic mechanism of transcriptional regulation.
Basic knowledge on chromatin structure, the nucleosome and higher-order chromatin structure.
Principles of Epigenetics: basic concepts on DNA methylation, histone post-translational modifications, the histone code hypothesis.
X-chromosome inactivation and imprinting.
Basic knowledge of neuroanatomy and neurophysiology.
Assessment methods and Criteria
For the BIO13 module only, learning will be assessed through the presentation of scientific articles in Journal Clubs held by small groups of students during the course and by means of a written examination with open questions at the end of the course. A written examination with open questions at the end of the course will be also applied at the end of the course for learning assessment concerning topics of MED03 module.

- Evaluation parameters will include i) specific knowledge of the subject, ii) familiarity with the relevant literature and ability to critically discuss each topic. In the written test, respect of formal and linguistic issues will be also considered.

- The final mark will be the result of the weighted average of BIO13 and MED03 marks considering 8 cfu for BIO13 and 6 cfu for MED03.
The final mark will be given on a 30 points basis (grades out of thirty) and the minimum passing mark is 18/30.
A positive evaluation for one of the two modules (BIO13 or MED03) will remain valid for the entire current academic year.
Examination results will be published in the Notice Board of the Ariel website.

ATTENDANCE: Attendance is required to be allowed to take the exam.
Biology
Course 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
Teaching methods
- Teaching methods used by the lecturers will include: a) frontal lessons; b) journal clubs; c) practical laboratory activities.

- Teaching material will be uploaded on the Ariel website and includes: a) pdf version of the teachers' presentations; b) scientific articles relevant to the covered topics; c) web books; d) videos; e) exercises.

- Attendance is compulsory.
Teaching Resources
"Human Molecular Genetics" Tom Strachan IV edition - Ed. Zanichelli
"Genetics and Genomics in Medicine" Tom Strachan - Ed. Garland www.garlandscience.com/ggm
Genetics in Medicine, Thompson &Thompson
Bibliographic references covering the topics presented and additional teaching material will be provided by the teachers during the course using the Ariel website
Medical genetics
Course syllabus
Medical Genetics
GENOMIC DISORDERS
1. Recurrent and non-recurrent genomic rearrangements and disease traits
2. Copy Number variation: from inter-individual genetic variability to disease
3. Array CGH for the analysis of constitutional genomic rearrangements. How interpret the findings

CNVS SIGNIFICANCE ASSESSMENT FLOW CHART: CASE STUDIES
Learning activities through acquisition, inquiry, collaboration, discussion and production

GENOMIC IMPRINTING AND RELATED SYNDROMES
1. The 15q11.2-13 imprinted region and related syndromes (Prader-Willi and Angelman syndromes)
2. 11p15.5 related syndromes (Beckwith-Wiedemann, Silver Russell syndrome, IMAGE)
3. Multilocus Imprinting Disorders

MOSAICISM IN HUMAN DISEASES: FROM CNVS TO SNVS

PRINCIPLES OF MOLECULAR DISEASES
1. Effect of mutations on protein function
2. Examples of Mendelian disorders illustrating mechanism by which mutations produce disease in different classes of proteins

Exploring Single Nucleotide Variants (SNVs) effect
Learning activities through acquisition, inquiry, collaboration, discussion and production

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

FROM MONOGENIC TO "COMMON" DISEASES
Type 2 Diabetes

THE POSITION EFFECT: WHEN THE MUTATION DOES NOT AFFECT CODING GENE SEQUENCES
MITOCHONDRIAL MEDICINE
1. Mitochondria and mitochondrial (dys)functions
2. Mitochondrial disorders caused by defects of nuclear DNA
3. Mitochondrial disorders caused by defects of mtDNA
4. Mitochondrial dysfunctions in neurodegenerative diseases
5. Case studies: patients with mtDNA mutations (point mutations or mtDNA deletion/depletion) vs patients with nuclear mutations

CANCER GENETICS
1. Sporadic and inherited cancer predisposition
2. Ovarian and breast cancer predisposition
3. Li-Fraumeni syndrome, Cowden syndrome
4. Colon cancer predisposition syndromes
5. MEN syndromes
6. Renal cancer predisposition

NEUROMUSCULAR DISORDERS
1. Muscular dystrophies
2. Spinal Muscular Atrophy
3. Amyotrophic Lateral Sclerosis
4. New therapeutic approaches for neuromuscular disorders

CASE DISCUSSION

MOLECULAR THERAPIES
1. Main principles of gene therapy
2. Modulation of gene expression
3. Induction of Exon Skipping/Retention - Splicing modulation (ASO)
4. Gene Editing (CRISPR/Cas9)
5. Gene therapy vs. gene editing

Practical laboratory activities
'Methods for the identification of DNA sequence variations'
LECTURES
1. Overview of the main techniques for the detection of point mutations, small deletions and small insertions
2. Direct Sanger sequencing and microsatellite analysis by capillary electrophoresis
3. Methylation-specific PCR

PRACTICAL LABORATORY ACTIVITIES
1. PCR amplification of genomic DNA fragments
2. Analysis of PCR fragments by gel electrophoresis
3. Direct Sanger sequencing
4. Microsatellite analysis
5. Methylation-specific PCR
6. Real-Time PCR
Teaching methods
Teaching methods used by the lecturers will include: a) frontal lessons.
- Teaching material will be uploaded on the Ariel website and includes: a) pdf version of the teachers' presentations; b) scientific articles relevant to the covered topics; c) web books; d) videos; e) exercises.

- Attendance is compulsory.
Teaching Resources
"Human Molecular Genetics" Tom Strachan IV edition - Ed. Zanichelli
"Genetics and Genomics in Medicine" Tom Strachan - Ed. Garland www.garlandscience.com/ggm
Genetics in Medicine, Thompson &Thompson
Bibliographic references covering the topics presented and additional teaching material will be provided by the teachers during the course using the Ariel website
Biology
BIO/13 - EXPERIMENTAL BIOLOGY - University credits: 8
Practicals: 24 hours
Lessons: 45.5 hours
Medical genetics
MED/03 - MEDICAL GENETICS - University credits: 6
Lessons: 42 hours
Professor(s)
Reception:
Appointment upon request
Dept. Medical Biotechnology and Translational Medicine, Via F.lli Cervi 93, 20090 Segrate