Genetic Disorders Flashcards
Sickle-cell anemia is caused by a mutation in which chain of hemoglobin?
Beta chain
What is the product of FMR1? What is its function?
FMR protein (FMRP)
RNA binding protein associated with polysomes; regulate protein synthesis at synapses
Do chromosomal abnormalities have high or low penetrance?
High
Do Mendelian disorders have a high or low penetrance?
High
Why does sickling lead to decreased NO?
Released Hb binds to NO, thereby depleting it
What is a neurofibroma and what is it composed of?
Peripheral nerve sheath tumors composed of a mixture of Schwann cells and fibroblasts
People with 22q11.2 deletions are at an increased risk of:
Schizophrenia
Bipolar disorder
ADHD
What is a nondisjunction mutation?
Failure of two homologous chromosomes (or two sister chromatids) to separate at metaphase of meiosis I (or meiosis II/mitosis)
Define polymorphism
the occurrence of different forms among the members of a population or colony, or in the life cycle of an individual organism.
What does it mean when FMR1 is said to have “nonclassic inheritance”?
Mutations don’t cause loss of function
How is phenylketonuria inherited?
Autosomal recessive
What is the function of CTLA4?
Cytotoxic T-lymphocyte associated protein 4
Negative regulator of immune response
Describe the clinical presentation of PKU.
Postnatal growth retardation
Moderate to severe intellectual disability
Recurrent seizures
Hypopigmentation
Eczematous skin rashes
What are some of the lesser-known symptoms of Down syndrome aside from intellectual disability and physical abnormalities?
40% have congenital heart disease
Digestive problems
10-20x increased risk of leukemia
Abnormal immune responses of unknown etiology (thyroid autoimmunity and lung infections)
Degenerative neurological disorder similar to Alzheimer’s
What is the significance of “sticky patches” in HbS?
Causes aggregation of deoxygenated sites
Caused by hydrophobic reside being replaced with a hydrophilic residue
Aside from the brain, what is the other major location for FMRP expression?
Testes
What causes symptom onset in Amyloidosis?
Amyloid build-up impinging on neighboring structures
How many gene candidates have been implicated in Type 1 diabetes? Which ones are most important?
20-30
Insulin gene
HLA region on Chr 6p21
PTPN22
IL2RA
CTLA4
Characteristic physical appearances for Fragile X Syndrome are not always present. What are they when they ARE present?
Long face
Large jaw
Why can PKU cause seizures?
Accumulation of Phe inhibits amino acid transport across the blood-brain barrier
What are the two hallmark symptoms of Ehlers-Danlos syndrome?
Elastic skin that bruises easily
Overly flexible joints
95% of cases of Trisomy 21 are a result of _____. 4% of cases are caused by ______.
95%: three chromosome 21
4%: translocation of extra chromosomal material
What environmental exposures would be required for someone that has a genetic predisposition as a result of polymorphisms to develop Type 1 diabetes?
Hypersensitivity reactions
Certain autoimmune diseases (ex: Lupus)
Describe the clinical presentation of Neurofibromatosis I
Neurofibromas
Optic nerve gliomas
Lisch nodules
Cutaneous hyperpigmented macules
Most phenotypical characteristics are a result of ______.
interaction of multiple polymorphisms
What is the function of Ras?
Promotion of survival and proliferation
What is Amyloidosis?
Progressive degenerative disease characterized by fibrillar protein deposits
What are some serious internal complications of Ehlers-Danlos syndrome?
Colon rupture
Large blood vessel rupture
Cornea rupture or retinal detachment
Diaphragmatic hernia
What is the location of the FMR1 gene?
Xq27.3
Describe how FMR1 is mutated in Fragile X syndrome and what the result is.
Multiple tandem CGG repeats in the 5’ UTR
More repeats promote DNA methylation
Single mutation (monogenic) disorders follow what type of inheritance?
Mendelian
What are the similarities and differences between DiGeorge Syndrome and velocardiofacial syndrome?
Both involve deletion of 22q11.2
DGS: nonspecific facial changes, T-cell immunodeficiency, hypocalcemia
VCS: specific facial changes, mild immunodeficiency, cardiac defects
What subunits make up normal adult hemoglobin (HbA)?
α2β2
What are the two qualifiers for a complex multigenic disorder?
Familial clustering
Not monogenic or chromosomal
Genetically speaking, what is the reason for the range of different presentations of 22q11.2 deletion?
Variations in size and position of the deletion
Phenylketonuria develops as a result of a mutation in what gene? What reaction does it catalyze?
Phenylalanine hydroxylase
Phe –> Tyr
Why does sickling cause bone marrow proliferation?
Compensation for loss of RBCs
What is amyloid?
Deposits of misfolded proteins
The pain associated with sickle-cell can be masked as ________ in young children.
Osteomyelitis (bone infection)
A mutation in what gene is responsible for Fragile X syndrome?
Familial mental retardation 1 (FMR1)
What is the function of IL2RA?
T cell activation
What is DiGeorge Syndrome?
Part of a spectrum of disorders associated with chromosomal deletion of 22q11.2
A glioma is described as _____.
A mass of glial cells
What subunits make up sickle hemoglobin (HbS)?
α2βs2
Loss of neurofibromin would result in ______.
Unregulated cell growth
What enzyme does PTPN22 code for?
Lymphoid protein Tyr phosphatase
Describe the “vicious cycle” of sickle-cell
Blockages in blood vessels cause localized hypoxia, which induces HbS aggregation, which leads to blockages, which leads to localized hypoxia……………………………………………
What is the function of lysyl hydroxylase?
Cross-linkage of collagen fibers in the extracellular space
What is the function of neurofibromin 1?
Negative regulator of Ras; tumor suppressor
What are the primary effects of sickling?
Chronic hypoxia
Hemolytic anemia
Bone marrow hyperproliferation
Decreased NO (vasodilator)
Neurofibromatosis type I involves a mutation in what gene?
Neurofibromin
What is the cause of Trisomy 21?
Meiotic non-disjunction of chromosome 21
What is the function of procollagen N-peptidase?
Cleavage of propeptides from collagen after being secreted into the extracellular space.
Describe “penetrance”
Whether or not the variant genotype (that produces a phenotype) can be inferred on the basis of defined phenotypic criteria
What gene is mutated in Neurofibromatosis I?
Neurofibromin I (NF1)
What is the inheritance of neurofibromatosis?
Autosomal dominant
What are Lisch nodules?
Pigmented nodules of the iris
What are the most common organs to experience vaso-occlusion due to sickled RBCs? Why?
Kidney, lung, spleen, liver
Large amount microvasculature
What subunits make up fetal hemoglobin (HbF)?
α2γ2
More than ____ disease-associated PAH alleles have been discovered, yet only a mutation in ____ will cause PKU.
500; 1
Define “opsonization”.
Binding of antibodies and complement molecules to allow recognition by phagocytes
What is the result of DNA methylation?
Represses DNA expression by reducing availability for transcription
Packages chromatin
What mutations could give rise to Ehlers-Danlos syndrome?
Mutations in collagens I, III, and V
Lysyl Hydroxylase
Procollagen N-Peptidase
Which gene on the deleted region (22q11.2) is thought to be responsible for DiGeorge syndrome? What does it do?
TBX1
Transcription factor that targets PAX9, which is associated with the palate, parathyroid, and thymus
How does the number of CGG repeats in the FMR1 gene vary between the normal population, affected individuals, and carriers?
Normal population: 6-55
Carriers: 50-200
Affected: 200-400
What is the primary phenotype of Fragile X Syndrome?
Intellectual disability
