X-Linked Recessive Inheritance and Mitochondrial Diseases

Question 1

In X-linked recessive disorders:

Answer 1

• Incidence of the trait is mostly in males (Occasionally female carriers will express it due to X-inactivation)
• There is no male to male transmission of the trait
• The trait is transmitted from an affected father to all his daughters (Daughters are usually obligate carriers, they do not express the disorder)
• Carrier female will transmit the trait to half of their sons (who will be affected) and half of their daughters (who will likely be carriers)
• Disorders are generally severe with early onset
• If disorder is lethal (with a reproductive fitness of 0) and the disease is constant in the population, 1/3 of affected males will have a new mutation

Question 2

In X-linked dominant disorders:

Answer 2

• All the daughters and none of the sons of an affected father will be affected
• All offspring of an affected mother have a ½ chance of inheriting the allele
• Very rare phenomenon

Question 3

In the case of dominantly inherited diseases from the X chromosome, _______ of all females with an affected mother and _______ females of an affected father will display the trait

Answer 3

½

all

Question 4

in disorders where _______ is not greatly affected, female children can inherit a mutant allele from both parents and be homozygous for the _______ allele (ex. _______)

Answer 4

fitness
recessive
color blindness

Question 5

Color blindness can occur “full blown” in females, it is rare because

Answer 5

X-linked diseases in general are uncommon, so the likelihood of a carrier and affected individual producing affected offspring is low

Question 6

_______ can also result in a female having the “full blown” disease.

Answer 6

Translocation of a portion of an autosome onto a mutant X chromosome

Question 7

As the _______ is required for survival, the X without the _______is preferentially inactivated, resulting in expression of the mutant X chromosome with its _______(ex. The gene associated with Duchene Muscular Dystrophy was discovered by studying rare cases of females with DMD).

Answer 7

autosome
autosomal translocation
autosomal translocation

Question 8

phenotypic expression of carrier females can depend on their pattern of _______. In some females, the _______ can be unbalanced or skewed, resulting in more cells expressing a mutant X than a normal X.

Answer 8

pattern of X-inactivation

X inactivation

Question 9

genes can have varying _______ and _______ depending on the mechanism of action of the gene product (ex. _______)

Answer 9

• penetrance and expressivity
• almost half of female carriers for Fragile X syndrome show some developmental abnormalities versus Hunter syndrome, where normal X gene products are able to rescue the cells expressing the mutant X).

Question 10

Why are about 1/3rd of the individuals who inherit an X-linked recessive disorder that is eventually lethal, considered to be new mutations?

Answer 10

If the fitness of males who have a X-linked disorder is near zero or lethal early in life, then those males are not capable of reproducing. Males carry 1/3 of the total X chromosomes while women carry 2/3 of all X chromosomes. Assuming the incidence of the disease is constant, that means 1/3 of the affected X chromosomes are always being lost due to death of the affected male. In order to maintain the constant disease level, 1/3 of mutations in affected males must therefore be spontaneous mutations not inherited from either parent.

Question 11

What are the clinical, biochemical/cytogenetic and molecular features of red/green colorblindness?

Answer 11

Caused by a defective red or green pigment gene that is located on the X chromosome. There is one red pigment gene and two green pigment genes both within the same locus control region that only allows two genes to be transcribed. In addition, these genes have very similar sequence (98% homology) and thus are at risk for aberrant recombination. If there is intragenic recombination, there are hybrid gene products that do not function normally. If there is intergenic recombination, gene copy number can change or be lost, resulting in a missing gene product.

Question 12

What are the clinical, biochemical/cytogenetic and molecular features of hemophilia A?

Answer 12

This disease is caused by a defect in Factor VIII which is a critical protein in the blood clotting cascade. Patients with this disease cannot convert prothrombin into thrombin. Factor VIII is coded for on the F8 gene on the X chromosome. Mutations of F8 include deletions, insertions, inversions and point mutations. The most common mutation is an inversion that deletes the C-terminus of Factor VIII and accounts for about 25% of all hemophilia and 40% of all severe cases. It is the result of an intragenic inversion due to homology between intron 22 and the sequences telomeric to F8.

Question 13

What are the clinical, biochemical/cytogenetic and molecular features of Duchenne muscular dystrophy?

Answer 13

A disease caused by a mutation in the DMD gene results in mutant dystrophin protein. This is a structural protein that anchors the actin and myosin elements of the cytoskeleton to the inside of the plasma membrane. The DMD gene is very large and complex with 79 exons making it more prone to mutation by simply being a larger target. Most mutations in the DMD gene are deletions that result in a frame shift and result in a truncated and completely non-functional dystrophin protein. There is a milder form of muscular dystrophy associated with the DMD gene resulting from an in frame mutation called Becker’s Muscular Dystrophy

Question 14

What are the clinical, biochemical/cytogenetic and molecular features of Fragile-X syndrome?

Answer 14

Caused by a mutation in the FMR1 gene on the X chromosome that produces a gene product important to neurons. It may be a chaperone protein that regulates mRNAs from the nucleus to the translational machinery. This gene contains a triplet repeat sequence in its 5’ UTR. Most FMR1 mutations are expansions of this CGG sequence. Normally, there are 6-50 of these repeats, but in affected individuals there are over 200 copies. The CpG elements of this sequence enhance DNA methylation in the promoter region of the gene. This silences transcription of the downstream gene products. The result of the triplet expansion and associated methylation results in a constricted appearance near the distal end of the X chromosome (at Xq27). People with 50-200 copies of the repeat have a permutation (this is genetic anticipation). The length of the triplet repeat gets longer with each generation it is transmitted by a female, whereas permutations often shorten in paternal transmission.

Question 15

What are the characteristic features of Maternal Inheritance pedigrees? What genetic material is mutated? Clinical symptoms of these diseases are usually restricted to which tissues?

Answer 15

In maternally inherited diseases, all the offspring of a female carrying the mutation will have the mutation and be affected. In this case, it is mitochondrial DNA that is mutant, as effectively all mitochondrial DNA is donated by the mother during fertilization. Since it is mitochondrial DNA, these disorders are associated with mitochondrial oxidative phosphorylation (i.e. the electron transport chain in the mitochondrial membrane) and affect tissues that have high energy demands. Brain, eye, muscle, heart, kidney and liver are commonly affected