Study Content and Questions for Chapter 24 Medical Genetics

Be able to explain why it is important to understand genes and the interaction of genes with environment both for normal health and disease.

• The cause of the illness can be determined and if it was inherited or not

  • Ex: is it pathogenic? A toxin in the environment? Or is it genetic?

Be able to explain that under healthy conditions, genes encode proteins that play important roles and perform important functions to maintain normal cellular processes. Mutations in genes (leading to loss of function, gain of function, etc) may lead to diseased states.

• Mutagens: Pollutants that are in the environment that alter your DNA sequence.

  • Ex: chemicals in change smoke to cancer.

• Gene-Gene interaction- don't change DNA sequence, but cause a chain reaction and affects the function of the other gene

• Transcription Factors: Pollutants in environment can indirectly affect DNA sequence by altering transcription factors responsible for starting the process of using genes to make proteins that are needed for functions of the body.

• Epigenetics can alter your health by affecting the proteins that turn genes on/off.

  • Ex: The height reached by a tree at maturity is a phenotype that is strongly influenced by environmental factors, such as the availability of water, sunlight, and nutrients. Nevertheless, the tree's genotype still imposes some limits on its height: an oak tree will never grow to be 300 meters tall no matter how much sunlight, water, and fertilizer are provided.

Be familiar with the six characteristics that are associated with diseases that have a genetic basis. Given a list of statements pick the statement/statements that support or do not support genetic disease.

• When an individual exhibit a disease the disorder is more likely to occur in blood relatives than in the general population

• Identical twins share the disease more often than fraternal twins

• Disease does not spread to individuals sharing similar environmental situations

• Different populations tend to have different frequencies of the disease

• Disease tends to develop @ a character age

• Human disorder may resemble a genetic disorder that is already known to have a genetic basis in an animal

• Correlation is observed between a disease and a mutant human gene or a chromosomal alteration

How is inheritance of genetic disease best studied currently in humans.

Pedigree diagrams that show the relationship among members of a family, as well as their status w/ respect to a particular hereditary condition

Be able to list the five major inheritance patterns of traits or diseases controlled by single genes

1. An affected offspring usually has one or two affected parents

2. An affected individual with only one affected parent is expected to produce 50% affected offspring ( on average)

3. Two affected, heterozygous individuals have (on average) 25% unaffected offspring. The trait occurs with the same frequency in both sexes

4. For most dominant, disease- causing alleles, the homozygote is more severely affected with the disorder. In some cases, a dominant allele may be lethal in the homozygous condition.

5. Autosomal dominant, autosomal recessive, X-linked dominant, X-linked recessive, and Y linked

What is consistent with Autosomal Recessive Inheritance?

Frequently, an affected offspring will have two unaffected parents; When two unaffected heterozygotes have children, the percentage of affected children is (on average) 25%; Two affected individuals will have 100% affected children; The trait occurs with the same frequency in both sexes

What characterizes Autosomal Recessive Inheritance?

• Disorders that involve defective enzymes typically have an autosomal recessive mode of inheritance

  • The heterozygote carrier has 50% of the functional enzyme

What is consistent with Autosomal Dominant Inheritance?

An affected offspring usually has one or both affected parents; An affected individual with only one affected parent is expected to produce (on average) 50% affected offspring; Two affected, heterozygous individuals will have (on average) 25% unaffected offspring; The trait occurs with the same frequency in both sexes; For most dominant disease-causing alleles, the homozygote is more severely affected with the disorder

What are some common expectations of Autosomal Dominant Inheritance?

• Haploinsufficiency: The heterozygote has 50% of the functional protein

  • This is not sufficient for a healthy (unaffected) phenotype

• Gain-of-function mutations: Mutation changes protein so it gains a new function

• Dominant negative mutations: The mutant gene product acts antagonistically to the wild-type gene product

What is consistent with X-Linked Recessive Inheritance?

Males are much more likely to exhibit the trait; The mothers of affected males often have brothers or fathers who are affected with the same trait; The mothers of affected males often have brothers or fathers who are affected with the same trait

What is consistent with X-Linked Dominant Inheritance?

Males are often more severely affected; Females may be less affected due to wild-type copy on the other X chromosome; Females are more likely to exhibit the trait when it is lethal to males; Affected mothers have a 50% chance of passing the trait to daughters

Select example of Autosomal Recessive Disorders, list genes, function of protein encoded by wild-type, and disease feature

Albinism (Type I)

• Gene: Tyrosinase

• Normal function: Makes melanin pigment

• Disease features: Very light skin, hair, eyes (little or no melanin)

Cystic Fibrosis (CF)

• Gene: CFTR

• Normal function: Chloride ion transport → regulates mucus thickness

• Disease features: Thick mucus, lung damage, digestive problems, salty sweat

Phenylketonuria (PKU)

• Gene: Phenylalanine hydroxylase

• Normal function: Breaks down phenylalanine (amino acid)

• Disease features: Neurological damage, intellectual disability if untreated; preventable by diet

Sickle Cell Disease

• Gene: β-globin

• Normal function: Makes normal hemoglobin → oxygen transport

• Disease features: Anemia, pain crises, blocked blood flow, organ damage

Tay-Sachs Disease

• Gene: Hexosaminidase A

• Normal function: Breaks down GM2 gangliosides in neurons

• Disease features: Progressive neurodegeneration → blindness → paralysis → early death

Select example of Autosomal Dominant Disorders, list genes, function of protein encoded by wild-type, and disease feature

Aniridia

• Gene: Pax6 (transcription factor)

• Normal function: Controls eye development during embryogenesis

• Disease features: Absence of iris → visual impairment → sometimes blindness

Achondroplasia

• Gene: FGFR3 (Fibroblast Growth Factor Receptor 3)

• Normal function: Regulates bone growth and development

• Disease features: Short stature, shortened limbs → most common cause of dwarfism

Marfan Syndrome

• Gene: Fibrillin-1

• Normal function: Provides elastic strength and structural support in connective tissue

• Disease features: Tall, thin body; long limbs; flexible joints; weak aorta → aneurysm risk

Familial Hypercholesterolemia

• Gene: LDL receptor

• Normal function: Removes LDL cholesterol from blood

• Disease features: Very high LDL → plaque buildup → early heart disease

Huntington Disease

• Gene: Huntingtin

• Normal function: Neuronal function and transport (exact role complex)

• Disease features: Progressive neurodegeneration → movement problems, cognitive decline, psychiatric symptoms

Select example of X-Linked Recessive Disorder, list genes, function of protein encoded by wild-type, and disease feature

Duchenne Muscular Dystrophy (DMD)

• Gene: Dystrophin

• Normal function: Anchors muscle fibers to the cytoskeleton → structural stability during contraction

• Disease features: Progressive muscle degeneration, childhood onset, loss of ambulation, early death

Hemophilia A

• Gene: Clotting factor VIII

• Normal function: Blood coagulation cascade → clot formation

• Disease features: Excessive bleeding, poor clotting, hemorrhage risk

Hemophilia B

• Gene: Clotting factor IX

• Normal function: Blood coagulation cascade → clot formation

• Disease features: Same as Hemophilia A → defective clotting

Androgen Insensitivity Syndrome (AIS)

• Gene: Androgen receptor

• Normal function: Responds to testosterone → male sexual development

• Disease features: XY individuals:

  • Female external appearance

  • Undescended testes

  • No uterus

  • No functional male reproductive organs

Select example of X-Linked Dominant Disorder, list genes, function of protein encoded by wild-type, and disease feature

Vitamin D–Resistant Rickets

• Gene: Metallopeptidase

• Normal function: Bone mineral regulation and phosphate metabolism

• Disease features: Poor bone mineralization → rickets → bone deformities → short stature

Rett Syndrome

• Gene: MeCP2 (methyl-CpG-binding protein 2)

• Normal function: Regulates gene expression in neurons

• Disease features: Severe neurodevelopmental disorder, slowed head growth, small hands & feet, intellectual disability; fatal in males

Aicardi Syndrome

• Gene: Unknown

• Normal function: Unknown

• Disease features: Partial or complete absence of corpus callosum, retinal abnormalities, severe neurological defects; fatal in males

Incontinentia Pigmenti

• Gene: NF-κB essential modulator

• Normal function: Controls immune signaling & cell survival

• Disease features: Skin pigmentation abnormalities, dental defects, hair & nail abnormalities; fatal in males

Loss of function in genes for which kind of proteins are typically associated with autosomal recessive disorders?

enzymes

What is Huntington’s disease, how is it inherited? What is the molecular basis of this disease that is known to be inherited in an autosomally dominant manner?

• The major symptom of the disease is the degeneration of certain types of neurons in the brain

  • This leads to personality changes, dementia, and early death (usually in middle age)

• The mutation adds a polyglutamine tract to the protein

  • This causes an aggregation of the protein in neurons

• HD is inherited in an autosomal dominant manner

  • only one copy of the defective HTT gene is needed to cause the disease

Locus heterogeneity

• Refers to the phenomenon that a disease can be caused by mutations in two of more different genes

• Ex: Hemophilia

  • Blood clotting involves a cellular cascade that involves several different proteins

  • Therefore, a defect in any of these proteins can cause the disease