Etty Widayanti, SSi. MBiotech.

Sub Bagian Biologi Bagian Anatomi

Fakultas Kedokteran

Universitas YARSI, JakartaNov 09

Lethal dominant

Juvenile amaurotic idiocyInfantile amaurotic idiocy

HistidinemiaHepatic fibrosis

Ichtyosis congenitaPolycistic kidney

Neuropathic (Gaucher diseases)Tyrosinemia

Sickle cell anemiaCystic fibrosis

Duchene muscular dystrophyHemophilia

Xeroderma pigmentosaAchondroplasiaThalassemiaEpiloiaAnonychia

Huntington’s diseases (HD)BrachydactylyRetinoblastoma

Sublethal dominant

Lethal recessive

Sublethal recessive

What is What is Huntington’s Huntington’s diseases diseases ((Huntington’s choreaHuntington’s chorea)?)?

Huntington’s chorea is a neurodegenerative disease characterized Huntington’s chorea is a neurodegenerative disease characterized by motor, cognitive, and emotional symptoms.by motor, cognitive, and emotional symptoms.

The cells of the basal ganglia, caudate nucleus and cortex of the The cells of the basal ganglia, caudate nucleus and cortex of the brain are specifically targeted in HD.brain are specifically targeted in HD.

HH = lethalHh = Huntington’s chorea (HD)Hh = normal

The age of onset for symptoms is generally 30-50 yearsThe age of onset for symptoms is generally 30-50 years

Huntington’s Disease is caused by a gene mutation that creates Huntington’s Disease is caused by a gene mutation that creates excess copies of the CAG codon which genetically program the excess copies of the CAG codon which genetically program the degeneration of the neurons of the brain.degeneration of the neurons of the brain. A triplet (CAG) is A triplet (CAG) is repeated 20-50 times in asymptomatic individuals; having more repeated 20-50 times in asymptomatic individuals; having more than 50 repeats is associated with disease symptoms. than 50 repeats is associated with disease symptoms.

The number of CAG codons varies and so does the severity of the The number of CAG codons varies and so does the severity of the diseasedisease

It is an Autosomal Dominant diseaseIt is an Autosomal Dominant disease

nnot sex-linkedot sex-linked

What causes HD?

Mood SwingsMood Swings

Impaired Cognitive FunctionsImpaired Cognitive Functions

ChoreaChorea

What are the major effects of HD?

What is thalassemia?What is thalassemia?

Genetic blood disorder resulting in a mutation or Genetic blood disorder resulting in a mutation or deletion of the genes that control globin deletion of the genes that control globin production.production.

Normal hemoglobin is composed of 2 alpha and 2 Normal hemoglobin is composed of 2 alpha and 2 beta globinsbeta globins

Mutations in a given globin gene can cause a Mutations in a given globin gene can cause a decrease in production of that globin, resulting in decrease in production of that globin, resulting in deficiencydeficiency

aggregates become oxidized aggregates become oxidized damage the cell damage the cell membrane, leading either to hemolysis, ineffective membrane, leading either to hemolysis, ineffective erythropoiesis, or both. erythropoiesis, or both.

2 types of thalassemia: alpha and beta2 types of thalassemia: alpha and beta..

mutation of 1 or more of the 4 alpha globin genes on mutation of 1 or more of the 4 alpha globin genes on chromosome 16chromosome 16

severity of disease depends on number of genes affectedseverity of disease depends on number of genes affected results in an results in an excess of beta globinsexcess of beta globins

Alpha ThalassemiaAlpha Thalassemia

Alpha Thalassemia TraitAlpha Thalassemia Trait

2 functional globin genes2 functional globin genes results in smaller blood cells that are lighter in colourresults in smaller blood cells that are lighter in colour no serious symptoms, except slight anemiano serious symptoms, except slight anemia

Silent Carriers (heterozygotes +/-)Silent Carriers (heterozygotes +/-)

3 functional alpha globin genes3 functional alpha globin genes No symptoms, but thalassemia could potentially No symptoms, but thalassemia could potentially

appear in offspringappear in offspring

1 functional globin gene1 functional globin gene results in very lightly coloured red blood cells and results in very lightly coloured red blood cells and

possible severe anemiapossible severe anemia hemoglobin H is susceptible to oxidation, therefore hemoglobin H is susceptible to oxidation, therefore

oxidant drugs and foods are avoidedoxidant drugs and foods are avoided treated with folate to aid blood cell productiontreated with folate to aid blood cell production

Alpha Thalassemia MajorAlpha Thalassemia Major

no functional globin genesno functional globin genes death before birth (embryonic lethality)death before birth (embryonic lethality)

Hemoglobin H DiseaseHemoglobin H Disease

Beta ThalassemiaBeta Thalassemia

mutations on chromosome 11mutations on chromosome 11 hundreds of mutations possible in the beta globin gene, hundreds of mutations possible in the beta globin gene,

therefore beta thalassemia is more diversetherefore beta thalassemia is more diverse results in results in excess ofexcess of alpha globinsalpha globins

slight lack of beta globinslight lack of beta globin smaller red blood cells that are lighter in colour due to lack of smaller red blood cells that are lighter in colour due to lack of

hemoglobinhemoglobin no major symptoms except slight anemiano major symptoms except slight anemia

Beta Thalassemia TraitBeta Thalassemia Trait

Beta Thalassemia IntermediaBeta Thalassemia Intermedia lack of beta globin is more significantlack of beta globin is more significant bony deformities due to bone marrow trying to make more bony deformities due to bone marrow trying to make more

blood cells to replace defective onesblood cells to replace defective ones causes late development, exercise intolerance, and high causes late development, exercise intolerance, and high

levels of iron in blood due to reabsorption in the GI tractlevels of iron in blood due to reabsorption in the GI tract if unable to maintain hemoglobin levels between 6 gm/dl – if unable to maintain hemoglobin levels between 6 gm/dl –

7 gm/dl, transfusion or splenectomy is recommended7 gm/dl, transfusion or splenectomy is recommended

Beta Thalassemia Major Beta Thalassemia Major complete absence of beta globincomplete absence of beta globin enlarged spleen, lightly coloured blood cellsenlarged spleen, lightly coloured blood cells severe anemiasevere anemia chronic transfusions required, in conjunction with chronic transfusions required, in conjunction with

chelation therapy to reduce iron (desferoxamine)chelation therapy to reduce iron (desferoxamine)

Sickle cell anemia is one of the most prevalent genetic Sickle cell anemia is one of the most prevalent genetic disorders world-widedisorders world-wide

Results from a variant of the Beta Globin gene on Results from a variant of the Beta Globin gene on chromosome 11 chromosome 11 – a glutamic acid at the 6a glutamic acid at the 6thth position is replaced by a valine position is replaced by a valine

resulting in formation of Hemoglobin Sresulting in formation of Hemoglobin S

Sickle cell anemia

Hemoglobin S

Sickled RBC’s are thick and clump together. Sickled RBC’s are thick and clump together.

RBC’s do not move freely through the blood RBC’s do not move freely through the blood vessels causing stasis and further sickling vessels causing stasis and further sickling to occur. to occur.

Blood flow stops and the tissue distal to the Blood flow stops and the tissue distal to the blockage becomes ischemic thus causing: blockage becomes ischemic thus causing: acute pain, cell destruction.acute pain, cell destruction.

Red blood cells Going through Red blood cells Going through VesselsVessels

People who have Sickle Cell have People who have Sickle Cell have sickle shaped red blood cells, which sickle shaped red blood cells, which causes complications because the causes complications because the blood cells are not able to reach blood cells are not able to reach certain parts of the body.certain parts of the body.

Hemoglobin GeneHemoglobin Gene

The gene related to sickle The gene related to sickle cell anemia is the cell anemia is the hemoglobin gene (HBB). hemoglobin gene (HBB).

Hemoglobin contains iron Hemoglobin contains iron and transports oxygen and transports oxygen from the lungs to the from the lungs to the peripheral tissues. peripheral tissues.

The HBB protein is 146 The HBB protein is 146 amino acids long.amino acids long.

The HBB gene is found on The HBB gene is found on chromosome 11.chromosome 11.

Genetics of Sickle Cell Genetics of Sickle Cell

Sickle cell is an autosomal recessive disease. Sickle cell is an autosomal recessive disease. Therefore, the child can only get Sickle cell if both parents Therefore, the child can only get Sickle cell if both parents

are carriers, not if only one is and the other is normal. They are carriers, not if only one is and the other is normal. They have a 25% chance of getting it if both are carriershave a 25% chance of getting it if both are carriers

There will be different forms of Hemoglobin There will be different forms of Hemoglobin when there is a mutation in the beta subunit when there is a mutation in the beta subunit

25 % HbSS25 % HbSS50 % HbS

25 % normal HbA

There will be different forms of Hemoglobin when there is a mutation in the beta subunit

There are 4 protein subunits of Hemoglobin A

Sickle cell disease genotypesSickle cell disease genotypes Hemoglobin SS disease (homozygous sickle cell disease)Hemoglobin SS disease (homozygous sickle cell disease)

– Both Beta Globin alleles with the S mutationBoth Beta Globin alleles with the S mutation– Most common and most severe formMost common and most severe form

Hemoglobin SC diseaseHemoglobin SC disease– One Beta Globin with the S mutationOne Beta Globin with the S mutation– One Beta Globin with the C mutation (lysine at position 6)One Beta Globin with the C mutation (lysine at position 6)– Patients sickle and have disease-typically milder than SS Patients sickle and have disease-typically milder than SS

Hemoglobin S Beta 0 (null) ThalassemiaHemoglobin S Beta 0 (null) Thalassemia– One Beta Globin gene with the S mutationOne Beta Globin gene with the S mutation– One Beta Globin Gene with a severe thalassemia mutation (No production of One Beta Globin Gene with a severe thalassemia mutation (No production of

normal beta globin)normal beta globin)– Similar to SS disease Similar to SS disease

Hemoglobin S Beta Plus ThalassemiaHemoglobin S Beta Plus Thalassemia– One Beta Globin with the S mutationOne Beta Globin with the S mutation– One Beta Globin Gene with a mild thalassemia mutation (decreased but finite One Beta Globin Gene with a mild thalassemia mutation (decreased but finite

production of normal beta globin)production of normal beta globin)– Typically milder than SS diseaseTypically milder than SS disease

Sickle cell and malariaSickle cell and malaria

As you can see, the areas where Malaria is present and the Sickle Cell allele is present

are overlapping.

Distribution of the sickle cell allele

Distribution of Malaria

It is It is UnknownUnknown why people with the Sickle Cell why people with the Sickle Cell Trait are resistant to Malaria, but there are Trait are resistant to Malaria, but there are

several theories… several theories…

1.1. The carriers of Sickle Cell have some The carriers of Sickle Cell have some abnormal Hemoglobin, and when they abnormal Hemoglobin, and when they come in contact with the Malaria parasite come in contact with the Malaria parasite they become sickled. Then those cells go they become sickled. Then those cells go through the spleen, which eliminates the through the spleen, which eliminates the cells because of their sickle shape, so the cells because of their sickle shape, so the Malaria would be eliminated as well.Malaria would be eliminated as well.

2.2. The Sickle Cell trait causes the malaria to The Sickle Cell trait causes the malaria to stay in the body for an extended period of stay in the body for an extended period of time, so it is able to build up a defense to it.time, so it is able to build up a defense to it.

3. Because oxygen concentration is low in the spleen, and because infected cells often get trapped in the spleen, it is possible that they are destroyed in the spleen

4. The Malaria parasite produces an acid when it is inside of the red blood cells. This causes the red blood cells to polymerize, and the cells will sickle. These sickled cells are then destroyed when the blood cells go through the spleen.

HemophiliaHemophilia

Blood clotting impairedBlood clotting impaired

Recessive allele, Recessive allele,

hh carried on X carried on X cchromosomeshromosomes

X-linked recessive traitX-linked recessive trait

More common in malesMore common in males

A man with hemophilia marries a normal woman who is not a carrier. What is the chance their

children will inherit hemophilia? Hemophilia is X-linked recessive.

XH XH = Normal Female

XH Xh = Normal Female (Carrier)

Xh Xh = Hemophilic Female

XHY = Normal Male

XhY = Hemophiliac Male

Y

XH

Xh XH Xh

XH

XH Xh

XHY XHY

Genotypes2 XH Xh, 2XHy

Phenotypes2 Carrier Females

2 Normal Males

Probability

O% for Hemophilia

Background – cystic fibrosisBackground – cystic fibrosis

Background:Background: Cystic fibrosis (CF) is generally considered the Cystic fibrosis (CF) is generally considered the most common severe autosomal recessive disorder in the most common severe autosomal recessive disorder in the Caucasian population, with a disease frequency of 1 in 2,000 and Caucasian population, with a disease frequency of 1 in 2,000 and a carrier frequency of 1 in 20. The major clinical symptoms a carrier frequency of 1 in 20. The major clinical symptoms include chronic pulmonary disease, pancreatic insufficiency, and include chronic pulmonary disease, pancreatic insufficiency, and an increase in sweat electrolyte concentrations. an increase in sweat electrolyte concentrations.

The cause of the disease appears to be a mutation in the gene The cause of the disease appears to be a mutation in the gene encoding the cystic fibrosis transmembrane conductance encoding the cystic fibrosis transmembrane conductance regulator (CFTR), a membrane protein involved in transporting regulator (CFTR), a membrane protein involved in transporting ions across epithelial surfaces, such as the linings of the lungs and ions across epithelial surfaces, such as the linings of the lungs and intestines. intestines.

Background – cystic fibrosisBackground – cystic fibrosis

Several mutations have been identified as being associated Several mutations have been identified as being associated with a non-functional CFTR protein. The most common with a non-functional CFTR protein. The most common mutation, accounting for about 50% of CF cases, is called mutation, accounting for about 50% of CF cases, is called delta F508; it is a three-base deletion resulting in the loss delta F508; it is a three-base deletion resulting in the loss of a phenylalanine at position 508, in the ATP-binding of a phenylalanine at position 508, in the ATP-binding portion of the protein. portion of the protein.

DMD is an inherited disorder characterized by rapidly progressive muscle weakness which starts in the legs and pelvis and later affectsthe whole body.

It is also the most common form of muscular dystrophy and usually affects only boys, but in rare cases it can also affect girls.DMD occurs in approximatelly 1 out of 3500 males.

Duchenne muscular dystrophy also known as pseudohypertrophic muscular dystrophy or muscular dystrophy – Duchenne type

What is Duchenne muscular dystrophy?

DMD is caused by a change in the dystrophin gene (30% of the case). It is responsible for making the protein dystrophin which keeps muscles strong and healthy. This change is referred to as mutation.

When there is a mutation in the dystrophin gene, the protein dystrophin doesn’t work. The muscle cells become weak and they gradually break down.

The remainder (70%) are inherited.

What causes DMD ?

DMD is inherited in an X-linked recessive pattern.

Women normally have two X chromosomes and men have one X chromosome.

Women who carry the defective gene can pass an abnormal X on to their son and he will develop DMD.

Girls who inherit the DMD mutation from their mother also inherit anormal copy of the gene on the X chromosome from their father. These girls will be carriers Every time a carrier mother becomes pregnant, there are fourpossible outcomes :

Clinical FeaturesClinical Features Genotype of DMDGenotype of DMD

Females carry the DMD gene on the X Females carry the DMD gene on the X chromosome.chromosome.

Females are carriers and have a Females are carriers and have a 50% chance of transmitting the 50% chance of transmitting the disease in each pregnancy.disease in each pregnancy.

– Sons who inherit the Sons who inherit the mutation will have the mutation will have the disease.disease.

– Daughters that inherit the Daughters that inherit the mutation will be carriers.mutation will be carriers.

The DMD gene is located on the Xp 21 The DMD gene is located on the Xp 21 band of the X chromosome.band of the X chromosome.

Mutations which affect the DMD gene.Mutations which affect the DMD gene. 96% are frameshift mutations96% are frameshift mutations 30% are new mutations30% are new mutations 10-20% of new mutations occur 10-20% of new mutations occur

in the gametocyte (sex cell, will in the gametocyte (sex cell, will be pass on to the next be pass on to the next generation).generation).

The most common mutation are repeats The most common mutation are repeats of the CAG nucleotides.of the CAG nucleotides.

Symptomps usually appear before age 6 . Most boys with DMD walkalone at a later age than average.There is progressive muscle weakness of the legs and pelvis.The children may :

Fall frequentlyHave trouble running as fast as their friendsHave trouble climbing stairsHave trouble getting up from a chairDevelop big calvesFrequently walk on their toes with the heel off the groundBy age 10, braces may be required for walking, andBy age 12, most patients are confined to a wheelchair

Other symptoms are :•Scoliosis•Intellectual impairment (in approx. 30% of Duchenne

patients)•Fatigue•Contractures of heels, legs•Shows Gower sign : standing up with the aid of hands

pushing on knees

Symptomps :

REFERENCES

Emery, A.E.H. 1985. Dasar-dasar genetika kedokteran. Yayasan Essentia Medica, Yogyakarta.

Hartono, Suryadi, Sudarmo, R.S. And Romi, M.M. 2004. Buku pegangan kuliah: Genetika kedokteran. Bagian Anatomi Fakultas Kedokteran UGM, Yogyakarta.

Suryo. 2001. Genetika manusia. Gadjah Mada University

Press, Yogyakarta.

Suryo. 2001. Genetika strata 1. Gadjah Mada University Press, Yogyakarta