Single Gene Disorders

Front 1

What is the inheritance pattern of Familial Hypertrophic Cardiomyopathy?
When is it fatal?

Back 1

(Autosomal Dominant, thickness of left ventricle (more than 1.2” = fatal risk)

Front 2

What is the most common cause for familial hypertrophic cardiomyopathy?

Back 2

Familial inheritance and then De novo mutation of the gene (MYH7) that produces the β-myosin heavy chain;

Front 3

What is the function of this protein?

Back 3

Part of the myosin motor unit

Front 4

What are the function of these proteins in cardiac muscle contraction?

Back 4

Cardiac Troponin T = anchors troponins to tropomyosin;
Cardiac Myosin Binding Protein = Anchors myosin to titin

Front 5

Why do the mutated proteins of cardiac muscle cause hypertrophy?

Back 5

Sarcomere proteins enhance contractile function and cause hypertrophic cardiomyopathy

Front 6

What kind of disease is achondroplasia? What is its inheritance pattern and what does it effect?

Back 6

Mutation effects bone and CT growth/development.

Front 7

What do FGFs ultimately do to a cell after binding to its receptor?

Back 7

Fibroblast Growth Factors bind to receptors, FGFR, which have protein tyrosine kinase activity.
Tyrosine kinases dimerize and send signals into the cell, ultimately altering transcription.

Front 8

At what level does the FGFR mutation in achondroplasia effect the cell?

Back 8

Transcription

Front 9

What gene is mutated in achondroplasia?

Back 9

Fibroblast growth factor receptor 3 gene (FGFR3)

Front 10

What is the most frequent mutations causing achondroplasia?

Back 10

Glycine to Argine

Front 11

What kind of inheritance does achondroplasia exhibit?

Back 11

AD

Front 12

What proportion of achondroplasia mutations are “new mutations”?

Back 12

80% are new mutations
Note that most point mutations are paternal, and most non-disjunctions are maternal.
Therefore, this was probably caused by a mutation in the sperm.

Front 13

What happens to a homozygous individual for the mutated achondroplasia gene?

Back 13

Lethal, die before birth

Front 14

What is the cellular function of FGFR3?
What happens to the tyrosine receptors?

Back 14

FGFR3 negatively regulates bone growth.
Therefore, the mutation NEGATIVELY regulates bone growth by ACTIVATING the FGFR.
Dimerization of the receptors normally has them internalizing and degrading. In the mutation, they are recycled back to the membrane instead of being degraded.

Front 15

What is the genetic difference between hypochondroplasia, thanatophoric dysplasia and achondroplasia?

Back 15

Hypochondroplasia:
Lys-to-Asn

Thanatophoric dysplasia (lethal): Lys-to-glu
gain of function

Achondroplasia: Glycine to Argine

Front 16

What is craniosynostosis, what is it associated with, and why does it occur?

Back 16

Craniosynostosis refers to the premature fusion of the sutures (seams) that separate the skull bones. Achondroplasia
If 1 of these closes up prematurely, growth of the skull along the line of the suture is arrested.

Front 17

What is Allelic heterogeneity?

Back 17

Different alleles, aka different mutations in the same gene, have different phenotypes.

Front 18

Is Thanatophoric dysplasia a gain or loss of function?

Back 18

Gain

Front 19

What is the mode of inheritance in osteogenesis imperfecti?

Back 19

AD

Front 20

Why is it this kind of inheritance?

Back 20

mutations in amino acids

Front 21

What kind of mutation in collagen type I is usually lethal?
Why?
What is the name for this kind of osteogenesis imperfecti?

Back 21

Glycine substitutions – prevent collagen fibers to closely pack together, and is lethal.
The name is Type II OI – GLY Substitutions

Front 22

Mutations in what part of the gene are the most severe? Why?

Back 22

C terminal is worse than N terminus, because the triple helix of collagen starts wrapping around the C termini of the three collagen molecules

Front 23

Which osteogenesis imperfecti presents with a blue sclera?

Back 23

OI – TYPE I (type I collagen disrupted, mutations in AA other than GLYCINE)

Front 24

What three things characterize Ehlers-Danlos syndrome (EDS)?

Back 24

Large joint hypermobility, connective tissue fragility, skin hyperextensibility

Front 25

Why are some EDS autosomal dominant while others are autosomal recessive in their mode of inheritance?

Back 25

AD – bad structural PROTEIN; AR – bad ENZYME

Front 26

o A patient presenting with large joint hypermobility, cigarette paper scars, and skin hyperextensibility would have what kind of EDS?
What is the mutation?

Back 26

EDS Type I and II (classical EDS) caused by mutation in type V collagen or type I collagen

Front 27

What kind of EDS is the most often lethal form of EDS? Why is this case?

Back 27

Vascular type EDS, or EDS TYPE IV, Most lethal because major complications in arterial rupture, and rupture of colon, and uterus when pregnant.

Front 28

What is one kind of EDS that is a result of a defect in an enzyme that processes collagen? Which gene/enzyme is defective?

Back 28

Vascular, VEDS, mutations in the COL3AI gene that affects type III procollagen synthesis, secretion and structure

Front 29

What causes EDS VII? Why is removing this part of the collagen molecule so important?

Back 29

Defects in the conversion of type I procollagen to collagen, deletions of exon 6, which is the cleavage site for the N-protease, also defects in converting enzyme procollagen N-Protease

Front 30

What is the three things distinguishes Marfan Syndrome?

Back 30

Arachnodactyly – spider fingers; Ectopic lentis – displaced lens; Aortic aneurysm – aorta rupture

Front 31

What two cardiovascular problems often occur in Marfan Syndrome?

Back 31

Aorta rupture and mitral valve prolapse either mild (w/o mitral regurg) or severe (w/ mitral regurg)

Front 32

What kind of mutation is the most common cause of Marfan Syndrome?

Back 32

Mutations of Fibrinillin I gene (FBN1 gene) on chromosome 15

Front 33

How are the mutations causing Marfan Syndrome described? Why are they called this?

Back 33

Described based on what is happening to the gene, such as frameshift or nonsense mutations

Front 34

What is the underlying cause for hereditary hypophosphatemia?

Back 34

Abnormally low levels of phosphate in the blood causing softening of the bones

Front 35

What three genes are involved in hypophosphatemia and how are they interacting to cause this disease?

Back 35

NPT2 is the sodium-phosphorus cotransporter whose synthesis is regulated by PHEZ and FGF23; PHEX is a protease that inactivates the inhibitor (PNT) of the synthesis of the NPT2; FGF23 inhibits the synthesis of NPT2 and the kidney enzyme that makes vitamin D; Involved with phosphate absorption from the intestines and reabsorption in the kidneys

Front 36

How is Thanatophoric dysplasia (lethel)
a gain of function?

Back 36

Gain of function mutant that is active in the absence of ligand.