16. Sex-linked and non-traditional inheritance

Question 1

Describe the Lyon Hypothesis

Answer 1

In females, there are two copies of each gene on the X chromosomes. One of these genes is inactivated resulting in what is called “dosage compensation”. This prevents overexpression of a gene.

Question 2

What are the 3 rules of dosage compensation?

Answer 2

1. Inactivation is random
2. Inactivation is fixed
3. Inactivation is INCOMPLETE

Question 3

Term given to the inactive X chromosome in females.

Answer 3

Barr Body

Question 4

The X-inactivation center is a region on an X chromosome that turns that chromosome into a barr body. How does this work?

Answer 4

This region contains a gene called XIST. Transcription of this gene creates mRNA that “walls off” the rest of the X chromosome so no polymerases can get to it. Prevents expression of the entire X chromosome.

Question 5

What is required for a female child to present with an X-linked recessive disorder. 2 things.

Answer 5

1. Mother must also be affected or a carrier

2. Father must be affected

Question 6

What type of genetic disorder is Hemophilia A and where is the defect in the genome?

Answer 6

1. X-linked recessive

2. Defect in Factor VIII gene

Question 7

What type of genetic disorder is Duchenne Muscular Dystrophy and where is the defect in the genome?

Answer 7

1. X-linked recessive (Becker MD is a milder form of this disorder)
2. Defect in dystrophin gene

Question 8

What is the function of the dystrophin protein?

Answer 8

Binds F-actin of the muscle cell’s contractile unit to dystroglycan, a membrane-bound protein.

Question 9

Physical exam test for Duchenne in which the physician instructs the child to stand up without any aid and the child has to use his (or her) hands to “walk up” their body from the seated position.

Answer 9

Gowers’ Sign

Question 10

Proteins that absorb color and can be mutated in Red/Green color-blindness. What causes this mutation?

Answer 10

1. Opsins

2. Unequal cross-over of genes that code for these proteins

Question 11

Name 2 major characteristics of X-linked dominant disorders.

Answer 11

1. Females 2x more likely to have disorder

2. Vertical transmission seen in every generation

Question 12

Name the 3 X-linked dominant disorders presented in class and a brief description of each.

Answer 12

1. Hypophosphatemic Rickets - kidneys cannot reabsorb phosphate and bones don’t calcify correctly
2. Incontinentia Pigmenti - abnormal skin and teeth pigment with neuro issues
3. Rett Syndrome - autism, ataxia, mental retardation

Question 13

How can a female be affected by Y chromosomal inheritance?

Answer 13

An affected father has a cross-over between homologs of his Y and X so that the X now carries the mutated gene.

Question 14

2 characteristics that indicate a mitochondrial inheritance genetic disorder.

Answer 14

1. Affected mother have 100% affected children

2. Affected fathers have NO affected children

Question 15

What is meant by mitochondrial inheritance displaying variable expression?

Answer 15

There are many mitochondria per cell, so the phenotypical presentation of the disorder depends on the number of affected mitochondria. This is heteroplasmy and some affected pts. will be more severe than others.

Question 16

Mitochondrial inherited disorder where the patients go blind in 3rd decade of life. What kind of mutation causes this?

Answer 16

1. Leber Hereditary Optic Neuropathy (LHON)

2. Missense Mutation

Question 17

Mitochondrial inherited disorder where patients have epilepsy, ataxia, dementia, myopathy. Very heteroplasmic. What type of mutation causes it?

Answer 17

1. Myoclonic Epilepsy w/ Ragged Red Fibers (MERRF)

2. Point Mutation in a tRNA gene

Question 18

Mitochondrial inherited disorder where patients have seizures, muscle weakness, and loss of apetite. Heteroplasmic. What type of mutation causes it?

Answer 18

1. Mitochondrial Encephalomyopathy and Stroke-Like Episodes (MELAS)
2. Point Mutation in a tRNA gene

Question 19

Describe the sherman paradox.

Answer 19

Deals with fragile X transmission. Normal males can transmit a fragile X but their children are not affected. Only his granchildren from one of his daughters can present with the disease.

Question 20

Mutated gene that has a high number of repeats and leads to Fragile-X Syndrome.

Answer 20

FMR-1 gene (normal # of CGG repeats is 6-50. Disease manifest when repeats reach 50-230)

Question 21

How does a mutated FMR-1 gene cause the symptoms in a patient with fragile X?

Answer 21

FMR-1 influences mRNA distribution in neurons. Disruption mostly affects glutamate receptors.

Question 22

Name 2 disorders resulting from mutations in gemonic imprinting.

Answer 22

1. Prader Willi Syndrome (paternal)

2. Angelman Syndrome (maternal)

Question 23

How does genomic imprinting work? How can this lead to disease?

Answer 23

1. A child receives one chromosome from each parent. Certain genes are imprinted (blocked from being transcribed) in either the mother or father. This means that the gene on the chromosome opposite of the imprinting must work correctly for the child to have a normal phenotype.
2. Disease occurs if the child has a deletion in the chromosome that should express the normal gene and the imprinted gene cannot compensate for the deletion because it is imprinted.