Etty Widayanti, SSi. MBiotech.

Sub Bagian Biologi Bagian Anatomi Fakultas Kedokteran Universitas YARSI, Jakarta
Nov 09

Lethal dominant
Huntingtons diseases (HD) Brachydactyly Retinoblastoma Xeroderma pigmentosa Achondroplasia Thalassemia Sublethal Epiloia dominant Anonychia

Lethal recessive
Juvenile amaurotic idiocy Infantile amaurotic idiocy Histidinemia
Hepatic fibrosis Ichtyosis congenita Polycistic kidney Neuropathic (Gaucher diseases) Tyrosinemia Sickle cell anemia Cystic fibrosis Duchene muscular dystrophy Hemophilia

Sublethal recessive

What is Huntingtons diseases (Huntingtons chorea)?

Huntingtons chorea is a neurodegenerative disease characterized by motor, cognitive, and emotional symptoms. The cells of the basal ganglia, caudate nucleus and cortex of the brain are specifically targeted in HD.

HH = lethal Hh = Huntingtons chorea (HD) Hh = normal

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

What causes HD?

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

The number of CAG codons varies and so does the severity of the disease It is an Autosomal Dominant disease not sex-linked

What are the major effects of HD?

Mood Swings Impaired Cognitive Functions Chorea

What is thalassemia?
Genetic blood disorder resulting in a mutation or deletion of the genes that control globin production. Normal hemoglobin is composed of 2 alpha and 2 beta globins Mutations in a given globin gene can cause a decrease in production of that globin, resulting in deficiency aggregates become oxidized damage the cell membrane, leading either to hemolysis, ineffective erythropoiesis, or both. 2 types of thalassemia: alpha and beta.

Alpha Thalassemia
mutation of 1 or more of the 4 alpha globin genes on chromosome 16 severity of disease depends on number of genes affected results in an excess of beta globins

Silent Carriers (heterozygotes +/-)

3 functional alpha globin genes No symptoms, but thalassemia could potentially appear in offspring

Alpha Thalassemia Trait

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

Hemoglobin H Disease

1 functional globin gene results in very lightly coloured red blood cells and possible severe anemia hemoglobin H is susceptible to oxidation, therefore oxidant drugs and foods are avoided treated with folate to aid blood cell production

Alpha Thalassemia Major

no functional globin genes death before birth (embryonic lethality)

Beta Thalassemia
mutations on chromosome 11 hundreds of mutations possible in the beta globin gene, therefore beta thalassemia is more diverse results in excess of alpha globins

Beta Thalassemia Trait

slight lack of beta globin smaller red blood cells that are lighter in colour due to lack of hemoglobin no major symptoms except slight anemia

Beta Thalassemia Intermedia

lack of beta globin is more significant bony deformities due to bone marrow trying to make more blood cells to replace defective ones causes late development, exercise intolerance, and high levels of iron in blood due to reabsorption in the GI tract if unable to maintain hemoglobin levels between 6 gm/dl 7 gm/dl, transfusion or splenectomy is recommended

Beta Thalassemia Major

complete absence of beta globin enlarged spleen, lightly coloured blood cells severe anemia chronic transfusions required, in conjunction with chelation therapy to reduce iron (desferoxamine)

Sickle cell anemia

Sickle cell anemia is one of the most prevalent genetic disorders world-wide
Results from a variant of the Beta Globin gene on chromosome 11 a glutamic acid at the 6th position is replaced by a valine resulting in formation of Hemoglobin S Sickled RBCs are thick and clump together. RBCs do not move freely through the blood vessels causing stasis and further sickling to occur.

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

Hemoglobin S

Red blood cells Going through Vessels

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

Hemoglobin Gene

The gene related to sickle cell anemia is the hemoglobin gene (HBB). Hemoglobin contains iron and transports oxygen from the lungs to the peripheral tissues. The HBB protein is 146 amino acids long. The HBB gene is found on chromosome 11.

Genetics of Sickle Cell

Sickle cell is an autosomal recessive disease. Therefore, the child can only get Sickle cell if both parents are carriers, not if only one is and the other is normal. They have a 25% chance of getting it if both are carriers

There will be different forms of Hemoglobin when there is a mutation in the beta subunit
There are 4 protein subunits of Hemoglobin A

25 % normal HbA

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

50 % HbS

25 % HbSS

Sickle cell disease genotypes

Hemoglobin SS disease (homozygous sickle cell disease) Both Beta Globin alleles with the S mutation Most common and most severe form
Hemoglobin SC disease One Beta Globin with the S mutation One Beta Globin with the C mutation (lysine at position 6) Patients sickle and have disease-typically milder than SS Hemoglobin S Beta 0 (null) Thalassemia One Beta Globin gene with the S mutation One Beta Globin Gene with a severe thalassemia mutation (No production of normal beta globin) Similar to SS disease Hemoglobin S Beta Plus Thalassemia One Beta Globin with the S mutation One Beta Globin Gene with a mild thalassemia mutation (decreased but finite production of normal beta globin) Typically milder than SS disease

Sickle cell and malaria

Distribution of the sickle cell allele

Distribution of Malaria

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

It is Unknown why people with the Sickle Cell Trait are resistant to Malaria, but there are several theories
1.

2.

The carriers of Sickle Cell have some abnormal Hemoglobin, and when they come in contact with the Malaria parasite they become sickled. Then those cells go through the spleen, which eliminates the cells because of their sickle shape, so the Malaria would be eliminated as well. The Sickle Cell trait causes the malaria to stay in the body for an extended period of time, so it is able to build up a defense to it. 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 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.

3.

4.

Hemophilia
Blood clotting impaired Recessive allele, h carried on X chromosomes X-linked recessive trait More 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 Genotypes 2 XH Xh, 2XHy

XHY =
XhY =

Normal Male
Hemophiliac Male XH

Phenotypes 2 Carrier Females 2 Normal Males

XH
XH Xh XHY

Xh Y

XH Xh XHY

Probability O% for Hemophilia

Background cystic fibrosis

Background: Cystic fibrosis (CF) is generally considered the most common severe autosomal recessive disorder in the Caucasian population, with a disease frequency of 1 in 2,000 and a carrier frequency of 1 in 20. The major clinical symptoms include chronic pulmonary disease, pancreatic insufficiency, and an increase in sweat electrolyte concentrations. The cause of the disease appears to be a mutation in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), a membrane protein involved in transporting ions across epithelial surfaces, such as the linings of the lungs and intestines.

Background cystic fibrosis

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

What is Duchenne muscular dystrophy?

DMD is an inherited disorder characterized by rapidly progressive muscle weakness which starts in the legs and pelvis and later affects the 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 causes DMD ?

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 doesnt work. The muscle cells become weak and they gradually break down. The remainder (70%) are inherited.

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 a normal 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 four possible outcomes :

Clinical Features Genotype of DMD

Females carry the DMD gene on the X chromosome. Females are carriers and have a 50% chance of transmitting the disease in each pregnancy. Sons who inherit the mutation will have the disease. Daughters that inherit the mutation will be carriers. The DMD gene is located on the Xp 21 band of the X chromosome. Mutations which affect the DMD gene. 96% are frameshift mutations 30% are new mutations 10-20% of new mutations occur in the gametocyte (sex cell, will be pass on to the next generation). The most common mutation are repeats of the CAG nucleotides.

Symptomps :
Symptomps usually appear before age 6 . Most boys with DMD walk alone at a later age than average. There is progressive muscle weakness of the legs and pelvis. The children may : Fall frequently Have trouble running as fast as their friends Have trouble climbing stairs Have trouble getting up from a chair Develop big calves Frequently walk on their toes with the heel off the ground By age 10, braces may be required for walking, and By 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

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