anatomy

poorva

GeneticDisorders-2.pptx

Home >Biology homework help >Anatomy homework help >anatomy

Genetic Disorders

Srujana Rayalam DVM, PhD

Dept. of Pharmaceutical Sciences

PCOM-GA campus

PHAR 113G Anatomy, Physiology & Pathophysiology I

8/26/2020 10:31 AM

The information herein is for informational purposes only and represents the current view of Microsoft Corporation as of the date of this presentation. Because Microsoft must respond to changing market conditions, it should not be interpreted to be a commitment on the part of Microsoft, and Microsoft cannot guarantee the accuracy of any information provided after the date of this presentation. MICROSOFT MAKES NO WARRANTIES, EXPRESS, IMPLIED OR STATUTORY, AS TO THE INFORMATION IN THIS PRESENTATION.

Learning Objectives

Describe the mutation responsible for sickle cell anemia and understand the genetic inheritance pattern

State how newborn screening can limit the incidence of phenylketonuria

Describe the key features of genetic disorders: cystic fibrosis and Marfan syndrome

Explain how mutations in col1a1 gene cause different types of osteogenesis imperfecta and how a dominant negative effect can arise

Explain the inheritance pattern for mutations in hemophilia

Describe how expansion of trinucleotide repeats contributes to genetic disorders

Outline how multifactorial genetic disorders arise

Explain aneuploidy associated with Down syndrome

Explain how inheritance patterns for mitochondrial & nuclear DNA differ

Types of Inheritance Patterns

Single gene inheritance

Not very common

Types of patterns: Autosomal Dominant; Autosomal Recessive; X-linked Dominant and X-linked Recessive

Recessive inheritance is typical of mutations in enzymes – 50% normal enzyme usually enough

Dominant inheritance is typical of mutations in structural protein – 50% normal amount of protein is not enough

Multifactorial inheritance

Mitochondrial inheritance

Chromosome abnormalities

Sickle Cell Anemia

Autosomal recessive inheritance pattern

Homozygous HbS (HbSS) is called sickle cell anemia (SCA)

Normal hemoglobin - two α chains and two β chains.

The biochemical defect that leads to the development of HbS involves the substitution of valine for glutamic acid as the sixth amino acid in the β-polypeptide chain.

RBC life span – reduced from normal 120 to ~10 days resulting in the inability of bone marrow to catch-up with the loss

Hemolysis – free hemoglobin inactivated NO causing vasoconstriction

Sickle Cell Anemia

1 in 10 carrier in African American population

Hypoxia triggers polymerization of Hb

Certain endemic areas in Africa – sickling of RBC protection against malaria

Other mutations on Hb gene (no sickling)

HbC: Glutamic acid replaced by lysine

Thalassemia: Defects in either alpha or beta chains of Hb – abnormal Hb resulting in anemia

Thalassemia major (homozygous for mutated allele)

Thalassemia minor (carrier/heterozygous)

Sickle cell gene inheritance scheme

(Example)

Pathophysiology

Robbins & Cotran Pathologic Basis of Disease (8th edition)

Pathophysiology

Phenylketonuria (PKU)

Characterized by abnormal phenylalanine metabolism → hyperphenylalaninemia

Autosomal recessive condition

Bi-allelic mutations of the gene encoding the enzyme phenylalanine hydroxylase (PAH)

PAH converts phenylalanine → tyrosine

PAH deficiency → accumulation of phenylalanine and its breakdown chemicals in the blood and body tissues

Phenylketonuria (PKU)

Excess phenylalanine or its metabolites contribute to the brain damage in PKU.

Affected infants are normal at birth but within a few weeks develop a rising plasma phenylalanine level → impairs brain development.

Excess phenylalanine is converted into phenylpyruvate (also known as phenylketone), which is detected in the urine.

A normal blood phenylalanine level is about 1mg/dl.

In cases of PKU, levels may range from 6-80mg/dl, but are usually greater than 30mg/dl.

Phenylketonuria (PKU)

Phenylalanine is an essential amino acid and is found in nearly all foods which contain protein, dairy products, nuts, beans, tofu… etc.

A low protein diet must be followed.

Individuals with PKU must be alert for food sweetened with aspartame.

Every state now screens the blood phenylalanine level of all newborns at about 3 days of age.

This test is one of several newborn screening tests performed before or soon after discharge from the hospital.

PKU- Inheritance Pattern

http://www.health.state.mn.us/divs/fh/mcshn/ncfu/cond/pku.htm

Cystic Fibrosis

A chronic, progressive, and frequently fatal genetic disease of the body’s mucus glands.

Primary defect due to abnormal function of an epithelial chloride channel protein encoded by the cystic fibrosis transmembrane conductance regulator (CFTR) gene on chromosome 7.

Although autosomal recessive, even heterozygote carriers have a higher incidence of respiratory and pancreatic diseases.

Ion transport disturbances in epithelial cells affects fluid secretion in exocrine glands and the epithelial lining of the respiratory, gastrointestinal, and reproductive tracts.

Common among Caucasians (especially Europeans), 1 in 20 are carriers.

Cystic Fibrosis

Mucoviscidosis

Mucus in CF patients is very thick and accumulates in the intestines and lungs.

The result is malnutrition, poor growth, frequent respiratory infections, breathing difficulties, and eventually permanent lung damage.

Lung disease is the usual cause of death in most patients.

Difficulty in breathing, pancreatic infections, sinus infection, cirrhosis of liver and infertility

Pathophysiology

CFTR regulates multiple additional ion channels and cellular processes.

The functions of CFTR are tissue-specific

sweat ducts, loss of CFTR function leads to ↓reabsorption of sodium chloride and production of hypertonic sweat

In respiratory epithelium, CFTR mutations result in loss or reduction of chloride secretion into the lumen

Various mutations grouped based on their effect on the CFTR protein

Robbins & Cotran Pathologic Basis of Disease (8th edition)

Clinical manifestations of mutations in the cystic fibrosis gene

Robbins & Cotran Pathologic Basis of Disease (8th edition)

Marfan Syndrome

Is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

Disorder of connective tissues, manifested principally by changes in the skeleton, eyes, and cardiovascular system.

Missense mutations in the FBN1 gene give rise to abnormal fibrillin-1, the major component of microfibrils found in the extracellular matrix.

Skeletal abnormalities are the most striking feature - unusually tall with exceptionally long extremities and long, tapering fingers and toes.

Osteogenesis Imperfecta

Due to variety of mutations in genes encoding subunits of type I collagen

Collagen

Most abundant protein in the body

Synthesized from fibroblasts

Type 1 collagen comprises 80% of total collagen in skin and muscle tissue

Composed of 2 chains of α1(I) collagen & 1 chain of α2(I) collagen that form a triple helix

Types I, II, III and V, and XI - fibrillar collagens

Type IV – basement membrane collagen

Types of Collagen

FIBRILLAR COLLAGENS
I	Ubiquitous in hard and soft tissues
II	Cartilage, intervertebral disk, vitreous
III	Hollow organs, soft tissues
V	Soft tissues, blood vessels
BASEMENT MEMBRANE COLLAGENS
IV	Basement membranes

Type I collagen is the only form of collagen in bone

Formation of Triple Helix in Collagen

Pathophysiology of Disease: an Introduction to Clinical Medicine (6th edition)

Triple-helical fibers comprise 2 chains of α1 & 1 chain of α2 collagen

Molecular pathogenesis of type I osteogenesis imperfecta

Presence of normal proα1(I) allele allows 50% reduced production of collagen

Disease phenotype relatively mild: Short stature, postnatal fractures, blue sclera, premature hearing loss

Dominant pattern of inheritance – 50% of normal type I collagen insufficient

Mutations in type I OI prevent expression of proα1(I) chain

Molecular pathogenesis of type II osteogenesis imperfecta

Collagen molecule has impaired function even with one normal proα1(I) chain - “Dominant negative” effect

Disease phenotype worse than type I osteogenesis imperfecta

Severe prenatal fractures & bone deformities, connective tissue fragility

Expression of defective protein worse than no expression from mutant allele

Mutations in type II OI cause defect in proα1(I) chain

Hemophilia

Hemophilia is the oldest known hereditary bleeding disorder.

Caused by a recessive gene on the X chromosome.

There are about 20,000 hemophilia patients in the United States.

One can bleed to death with small cuts.

The severity of hemophilia is related to the amount of the clotting factor in the blood. About 70% of hemophilia patients have less than one percent of the normal amount and, thus, have severe hemophilia.

Hemophilia

Hemophilia A

Royal diseases/Bleeding disease

Defective clotting factor VIII

More common

Hemophilia B

Christmas disease

Defective clotting factor IX

Less common

Hemophilia Genetic Inheritance

Fragile X-Associated Mental Retardation Syndrome

Second most common genetic cause of mental retardation

Inherited in X-linked dominant fashion

Caused by excessive number of CGG repeats in 5’-untranslated region of fmr1 gene

Number of trinucleotide (CGG) repeats varies (6–55) in normal individuals

A repeat size between 60 and 200 does not cause a clinical phenotype but is unstable and subject to additional amplification

Extensive expansion occurs during oogenesis (not during spermatogenesis)

Excessive number of repeats (>200) prevents transcription of fmr1 gene

Robbins & Cotran Pathologic Basis of Disease (8th edition)

Penetrance & expressivity tend to increase in successive generations due to expansion of trinucleotide repeats

Genetic Anticipation in Fragile X-Associated Mental Retardation Syndrome

Multifactorial Inheritance

Very common - many factors, both genetic and environmental are involved

Typically involve more common genetic variations called polymorphisms

Most are “single-nucleotide polymorphisms” – SNPs

Cause modest change in function (or expression) of particular protein

Do not cause overt disease, but modestly increase risk of disease

Examples of multifactorial traits and diseases include: height, neural tube defects, cancer, diabetes, asthma, coronary artery disease, hip dysplasia etc

Down Syndrome

Most common cause of mental retardation

Occurs in about 1 in 700 newborns in the USA

Two major genetic abnormalities associated with Down syndrome:

Nondisjunction of chromosome 21 during meiotic segregation, resulting in one extra chromosome 21 (trisomy 21), with 47 chromosomes on karyotyping.

Mostly involves extra maternal copy of chromosome 21

DNA rearrangement resulting in the fusion of chromosome 21 to another acrocentric chromosome via its centromere. This abnormal chromosome is called a robertsonian translocation chromosome. Unlike those with trisomy 21, these individuals have 46 chromosomes on karyotyping.

Prevalence increases with increasing age of mother

Relationship of Down syndrome to maternal age

Pathophysiology of Disease: an Introduction to Clinical Medicine (6th edition)

Amniocentesis data

Live births

Down Syndrome

Common features include developmental delay, growth restriction, congenital heart disease (in 50%), immunodeficiency, and characteristic major and minor facial and dysmorphic phenotypic features

Trisomy 21 causes 50% increase in the expression of many proteins encoded by chromosome 21

Unclear why this causes symptoms of Down syndrome

May be due to clusters of multiple genes in same biological pathway

Mitochondrial DNA

Each cell contains thousands of mitochondria, each containing copies of its DNA

Mitochondrial DNA is in larger quantities in a cell

Nuclear DNA is larger in size

Mitochondrial DNA is inherited from mother

Maternal Inheritance Pattern with Mitochondrial DNA

Summary

Sickle cell anemia

Phenylketonuria

Cystic fibrosis and Marfan syndrome

Osteogenesis imperfecta; dominant negative effect

Hemophilia

Expansion of trinucleotide repeats – genetic anticipation

Mitochondrial inheritance

Aneuploidy associated with Down syndrome

Multifactorial genetic disorders