Download Lecture 1-Genetics 1

Genetic Diseases 1
Dr. Nabila Hamdi
MD, PhD
Topics






Genetic Diseases
Hemodynamic Disorders
Cardiovascular Diseases
CNS
Liver
Hematopoietic System
Assessments
Student assessment methods
Quizzes
Assignments
Mid-term exam
Final exam
Assessment weight
20%
5%
30%
45%
Course materials Will be posted on PBT website: http://pbt.guc.edu.eg
Course instructor:
Dr. Nabila Hamdi
[email protected]
B3.114
2
ILOs
•
•
•
•
•
•
•
•
•
•
•
•
Define and use in proper context the genetic terminology.
Be able to describe the main modes of Mendelian and non-Mendelian inheritance.
Given a family history or pedigree, indicate the most likely mode of inheritance.
Understand the clinical implications of incomplete penetrance and variable
expressivity
Appreciate the risk of individuals suffering simple Mendelian disorders.
Be able to describe clinical features of common Mendelian diseases.
Be able to describe clinical features of common chromosomal disorders.
Understand the principles of cytogenetics and analysis of karyotypes.
Recall major types of structural chromosome abnormalities and their basic
implications.
Discuss and contrast examples of diseases following an atypical pattern of
inheritance.
Recognize the genetic and environmental contribution to multi-factorial
conditions.
To have a clinical knowledge of several Mendelian and chromosomal conditions.
3
Outline
I.
II.
NATURE OF GENETIC ABNORMALITIES CONTRIBUTING TO HUMAN DISEASE
MENDELIAN DISORDERS: DISEASES CAUSED BY SINGLE-GENE DEFECTS
1.
2.
3.
4.
5.
Transmission Patterns
Diseases Caused by Mutations in Genes Encoding Structural Proteins
Diseases Caused by Mutations in Genes Encoding Receptor Proteins
Diseases Caused by Mutations in Genes Encoding Channels
Diseases Caused by Mutations in Genes Encoding Enzyme Proteins
III.
IV.
COMPLEX MULTIGENIC DISORDERS
CYTOGENETIC DISORDERS
1.
2.
3.
Chromosomal Abnormalities
Cytogenetic Disorders Involving Autosomes
Cytogenetic Disorders Involving Sex Chromosomes
IV.
SINGLE-GENE DISORDERS WITH ATYPICAL PATTERNS OF INHERITANCE
1.
2.
Triplet Repeat Mutations
Diseases Caused by Mutations in Mitochondrial Genes
4
General Organization of the Human
Genome
Humans have only about 30,000 protein-coding genes, far fewer than the 100,000
previously estimated and almost half the number in the lowly rice plant!!
5
Phenotypic Diversity
“Polymorphisms”
Single Nucleotide
Polymorphisms (SNPs)
Copy Number Variations
(CNVs)
CNVs are responsible for 5 to 24
million base pairs of sequence
difference between any two
individuals
Less than 1% of SNPs occurs
in coding regions
http://www.wadsworth.org/events/genetics/
Any two individuals share greater than 99.5% of their DNA sequences.
Thus, the remarkable diversity of humans is encoded in less than 0.5% of our DNA.
6
Genetic Abnormalities Contributing to
Human Diseases
Mutations
(SNPs)
CNVs
Protein-Coding Genes
 Amplification
 Deletion
50% CNVs encompass gene coding sequences
leading to dosage imbalances
(phenotypic diversity, susceptibility to diseases)
Alterations in ncRNA
 Long non-coding RNAs (lncRNAs)
 MicroRNAs (miRNAs)
Epigenetic Changes
Modulation of gene expression in the
absence of alterations in DNA sequence
 Hypermethylation
 Histone modifications
7
Genetic Abnormalities Contributing to
Human Diseases
Mutations
 Point mutations (substitution of a single nucleotide base by a different base)
“Missense” mutations
(sickle cell anemia)
“Nonsense” mutations
(Thalassemia)
8
Genetic Abnormalities Contributing to
Human Diseases
 Frameshift mutations (addition or deletion of one or two base pairs)
No shift!!
 Trinucleotide repeat mutations
Cystic Fibrosis
• Fragile X syndrome: Increased tandem repeats of CGG within FMR1 gene.
• Huntington disease: Increased tandem repeats of CAG in a gene located on
4p16.3.
9
Mendelian Disorders
Diseases Caused by Single Gene Defects
(Anemia)
(Anemia)
(Anemia)
*Some variants of Ehlers-Danlos syndrome have an autosomal recessive inheritance pattern.
Biochemical Basis and Inheritance Pattern for
Selected Mendelian Disorders
10
Mendelian Transmission Patterns
??
Recurrence??
11
Human Genetics https://www.uic.edu/classes/bms/bms655/lesson4.html/
http://www.biologie.uni-hamburg.de/b-online/library/cat-removed/u4aos1p5.html
Mendelian Transmission Patterns
Recurrence??
12
Human Genetics https://www.uic.edu/classes/bms/bms655/lesson4.html/
http://www.biologie.uni-hamburg.de/b-online/library/cat-removed/u4aos1p5.html
Mendelian Transmission Patterns
 Disorders of Autosomal Dominant Inheritance
• Manifested in the heterozygous state.
• Both males and females are affected, and both can transmit the condition
(50% chance).
• Reduced penetrance: some persons inherit the mutant gene but are
phenotypically normal.
• Variable expressivity: a trait is consistently associated with a mutant gene but
is expressed differently among persons carrying the gene.
• The age at onset is delayed, and symptoms and signs do not appear until
adulthood.
• Proteins involved in regulation of complex metabolic pathways (LDL receptors)
and key structural proteins (collagen, fibrillin).
13
Mendelian Transmission Patterns
 Disorders of Autosomal Recessive Inheritance
•
Manifested in the homozygous state: when both of the alleles at a given gene
locus are mutants.
•
There are skipped generations.
•
The trait does not usually affect the parents, but siblings may show the disease
(consanguineous marriage!)
•
The recurrence risk is 25% for each birth.
•
Complete penetrance is common.
•
Onset is frequently early in life.
•
Enzyme proteins are affected: 50% loss of enzyme activity can be compensated
14
for.
Mendelian Transmission Patterns
X-linked Disorders
• All sex-linked disorders are X-linked.
• Most X-linked disorders are X-linked recessive
• Transmitted by heterozygous female carriers only to sons.
• Heterozygous females rarely express the full phenotypic change.
• Sons of heterozygous women have one chance in two of receiving the
mutant gene (50%).
• An affected male does not transmit the disorder to sons, but all daughters
are carriers.
15
Mendelian Disorders
1. Diseases Caused by Mutations in Genes
Encoding Structural Proteins
Marfan Syndrome
Ehlers-Danlos Syndromes
16
Marfan Syndrome
http://quizlet.com/2752374/connective-tissue-flash-cards/
•
Mutation affecting fibrillin: glycoprotein, secreted by fibroblasts, is the major component
of microfibrils found in the extracellular matrix.
•
Microfibrils serve as scaffolding for the deposition of tropoelastin, an integral component
of elastic fibers.
•
Microfibrils are particularly abundant in the aorta, ligaments, and the ciliary zonules that
17
support the ocular lens.
Marfan Syndrome
•
Fibrillin is encoded by the FBN1 gene, which maps to chromosomal locus 15q21.
•
Molecular diagnosis of Marfan syndrome is not yet feasible: more than 600 distinct
causative mutations in the very large FBN1 gene have been found.
•
Autosomal dominant with variable expressivity (it is believed to be related to different
allelic mutations in the FBN1 gene.
•
The prevalence of Marfan syndrome is estimated to be 1 per 5000.
•
Approximately 70% to 85% of cases are familial.
•
The rest are sporadic, arising from de novo FBN1 mutations in the germ cells of
parents.
18
“Spider fingers”
http://www.handresearch.com/diagnostics/marfan-syndrome-hand-test.htm
http://ratedmedicine.wordpress.com/high-arched-palate/
High-arched palate
http://www.hughston.com/hha/a_12_2_4.htm
http://temasek68.blogspot.com/2009_06_01_archive.html
Marfan Syndrome: Skeletal abnormalities
19
Marfan Syndrome
http://www.cardiachealth.org/mitral-valve-prolapse-mvp
Nucleus Medical Media, Inc.
http://www.hughston.com/hha/a_12_2_4.htm
Aortic aneurysm
Mitral valve prolapse
Aortic incompetence
Cardiovascular abnormalities
20
Marfan Syndrome
http://quizlet.com/3969760/3-orbit-and-eyeball-flash-cards/
Chapter 73 Cataract: Clinical Types
MANUEL B. DATILES III and BENJAMIN V. MAGNO
Bilateral dislocation, or subluxation, of the lens secondary to weakness of
its suspensory ligaments.
Occular problems
21
Marfan Syndrome
 Skeletal abnormalities
•
•
•
•
Elongated habitus with abnormally long legs, arms, and fingers.
High-arched palate and hyperextensible joints.
Spinal deformities, such as severe kyphoscoliosis.
Chest is deformed (deeply depressed or pigeon-breast)
 Ocular changes
Bilateral dislocation, or subluxation, of the lens secondary to weakness of
its suspensory ligaments.
 Cardiovascular system
•
•
•
•
Fragmentation of the elastic fibers in the tunica media of the aorta predisposes
to aneurysmal dilation and aortic dissection.
Dilation of the aortic valve ring, giving rise to aortic incompetence.
The cardiac valves, especially the mitral valve, may be excessively distensible and
regurgitant (floppy valve syndrome), giving rise to mitral valve prolapse and
congestive cardiac failure.
Aortic rupture is the most common cause of death.
Ehlers-Danlos Syndromes
http://quizlet.com/2752374/connective-tissue-flash-cards/
•
(EDSs) are a group of diseases characterized by defects in collagen synthesis or structure.
•
The mode of inheritance encompasses both autosomal dominant and recessive patterns.
•
There are approximately 30 distinct types of collagen which are the products of different
genes.
23
Elastic Man: Garry Turner
sets stretchiest skin record!
24
http://strange-wonders.blogspot.com/2012/05/elastic-man-garry-turner sets_10.html
Firestein: Kelley's Textbook of Rheumatology, 8th ed.
http://www.pregnancy-bliss.co.uk/ehlers-danlos-syndrome.html
25
Ehlers-Danlos Syndromes
• Tissues rich in collagen, such as skin, ligaments, and joints, frequently are
involved.
• The abnormal collagen fibers lack adequate tensile strength.
•
Skin is hyperextensible and joints are hypermobile.
• The skin is extraordinarily stretchable, extremely fragile, and vulnerable to
trauma.
• Minor injuries produce gaping defects, and surgical repair or any surgical
intervention is accomplished only with great difficulty.
• Wound healing is poor.
26
Ehlers-Danlos Syndromes
There are at least six clinical and genetic variants of EDS, among them:
 Kyphoscoliotic EDS (AR): Ocular fragility with rupture of the cornea and
retinal detachment, deficiency of the enzyme lysyl hydroxylase affects crosslinks among collagen molecules.
 Vascular EDS (AD): Rupture of the colon and large arteries, deficient
synthesis of type III collagen resulting from mutations affecting collagen III
gene.
 Classical EDS (AD): Diaphragmatic hernias, deficient synthesis of type V
collagen resulting from mutations affecting collagen V gene.
27
References
ROBBINS Basic Pathology 9th Edition
ROBBINS Basic Pathology 8th Edition
Source of the cover image:
http://www.biologyreference.com/Fo-Gr/Genetic-Diseases.html
28
Thank you…
29