Question from previous week In most recessive disorders Hetrozygosity can be detected using Biochemical Carrier Detection. Explain what Biochemical Carrier Detection could be.

………new models of medical practice are evolving, with increasing attention to primary care and preventative medicine. ………new models of medical practice are evolving, with increasing attention to primary care and preventative medicine. Genetics will play a central role in this new approach ……….. Today's medical student therefore face the dual challenge of mastering an ever complex body of knowledge along with the need to develop a set of problem solving skills that will foster career- long learning. Today's medical student therefore face the dual challenge of mastering an ever complex body of knowledge along with the need to develop a set of problem solving skills that will foster career- long learning.

It has been clear that the traditional lecture-based medical curriculum is not well suited to these needs, opening the door to new approaches to medical education. The problem-based approach has been the mainstay of curriculum change at many schools, including here at Harvard Medical School.

Sex-linked inheritance

James and Brenda, who are both in their mid twenties, are referred to the genetic clinic. They are considering starting a family but are concerned because Brenda has a half-brother, Chars (same mother, different father), who has Duchene's Muscular Dystrophy

This diagnosis was made at age 4, when Chares was evaluated for delayed language development. At that time it was noted that he had achieved motor milestones normally in the first year of life but had difficulty climbing stairs and was considered to be clumsy in preschool. A serum creatine phospokinase assay revealed a level of 11,000 mU/ml (normal < 30), and a muscle biopsy showed a pattern typical for Duchene's muscular dystrophy.

Duchene's Muscular Dystrophy Progressive loose of muscle strength Progressive loose of muscle strength X-linked recessive trait X-linked recessive trait Occurs mostly in males Occurs mostly in males Gower’s sign Gower’s sign Gradually Paralyzed Gradually Paralyzed Late cardiomyopathy  Cardiac failure Late cardiomyopathy  Cardiac failure Death in before twenties Death in before twenties

Creatine Phosphokinase (CPK) Increased levels of serum CPK even at birth Increased levels of serum CPK even at birth Not a definite test, muscle biopsy Not a definite test, muscle biopsy

Charles is now 18 years old. He has been wheelchair-bound since age 11 and has profound weakness of all proximal muscles. He has experienced several bouts of respiratory infections, the most recent of which required prolonged hospitalisation. His cognitive function is impaired as well (IQ test)

James and Brenda are concerned that they are at risk of having a child with DMD. Having read literature from the Muscular Dystrophy Association, they are also interested in knowing whether they could have a child with a milder disorder, Becker’s dystrophy

Becker’s dystrophy Same muscle group as in DMD are affected Same muscle group as in DMD are affected The age of onset is later The age of onset is later The rate of progression is slower The rate of progression is slower

Further investigation of the family history reveals that Brenda’s mother had a brother who also received diagnosis of DMD. He had died at age of 17 of pneumonia. Brenda’s mother has a healthy brother as well. No other family members are known to have muscle disease. No other family members are known to have muscle disease.

Write done your answer to James and Brenda concern Now

Dystrophin Maintaining the structural integrity of muscle cells Maintaining the structural integrity of muscle cells DMD gene was isolated in 1986 DMD gene was isolated in 1986 Is about 2.3 million base pairs of DNA (largest known human gene) Is about 2.3 million base pairs of DNA (largest known human gene) Contains at least 79 exons that produce a 14kb mRNA Contains at least 79 exons that produce a 14kb mRNA

Sex linked traits In addition to determining gender, X and Y chromosomes have different genes that have nothing to do with sex In addition to determining gender, X and Y chromosomes have different genes that have nothing to do with sex X-linked genes are on the X chromosome Y-linked genes are on the Y chromosome This results in different patterns of inheritance in females and males This results in different patterns of inheritance in females and males X-chromosomes are larger, they have more genes X-chromosomes are larger, they have more genes

Examples of X-linked traits – genes on the X chromosome Red-green colorblindness Red-green colorblindness َ (8% Caucasian males) Hemophilia Hemophilia (blood does not clot) Duchenne's muscular dystrophy (muscle weakness, early death) Duchenne's muscular dystrophy (muscle weakness, early death)

The eggs of the mother will contain either a normal X chromosome or an X chromosome with the mutation causing red-green color blindness. The sperm of the father will contain either the normal X chromosome or the Y chromosome.

None of the female children would be red-green color blind, but half would be "carriers." None of the female children would be red-green color blind, but half would be "carriers." Half of the sons would inherit the allele from their mother and be afflicted. Half of the sons would inherit the allele from their mother and be afflicted.

X inactivation Mary Lyon (early 1960s) hypothesis on inactivation of one of the X chromosomes (dosage compensation) EG. In Mice and Calico cat Mary Lyon (early 1960s) hypothesis on inactivation of one of the X chromosomes (dosage compensation) EG. In Mice and Calico cat X inactivation is randomly determined but fixed and incompleat X inactivation is randomly determined but fixed and incompleat Females  mosaics for X chromosome Females  mosaics for X chromosome Males  hemizygous for X chromosome Males  hemizygous for X chromosome

Evidence for X inactivation

X inactivation Mechanism There is at least 1 gene (XIST) in X inactivation center (Xic) of the X chromosome There is at least 1 gene (XIST) in X inactivation center (Xic) of the X chromosome It produces an mRNA of 15 to 17kb that coats the inactive chromosome It produces an mRNA of 15 to 17kb that coats the inactive chromosome Methylation also play an important role in X inactivation (GC dinucleotide repeats) Methylation also play an important role in X inactivation (GC dinucleotide repeats)

Questions for Sex linked inheritance subject 1) A man with hemophilia A (an x- linked recessive trait) has a daughter who is severely affected. How might this be explained? 1) A man with hemophilia A (an x- linked recessive trait) has a daughter who is severely affected. How might this be explained?

2- Calculate recurrence risk for: A) Heterozygous female × normal male A) Heterozygous female × normal male B) Affected male × normal female B) Affected male × normal female SonsDaughters Affected ? % Heterozygous carrier ? % Unaffected ? %

3) A human female "carrier" who is heterozygous for the recessive, sex-linked trait causing red-green color blindness (or alternatively, hemophilia), marries a normal male. What proportion of their male progeny will have red-green color blindness (or alternatively, will be hemophiliac)? 3) A human female "carrier" who is heterozygous for the recessive, sex-linked trait causing red-green color blindness (or alternatively, hemophilia), marries a normal male. What proportion of their male progeny will have red-green color blindness (or alternatively, will be hemophiliac)? A. 100%A. 100% B. 75%B. 75% C. 50%C. 50% D. 25%D. 25% E. 0%E. 0%

Fragile X syndrome (CGG Repeats)