Question from previous weekQuestion from previous week

In most recessive disorders In most recessive disorders Hetrozygosity can be detected using Hetrozygosity can be detected using

Biochemical Carrier Detection.Biochemical Carrier Detection.

Explain whatExplain what

Biochemical Carrier DetectionBiochemical Carrier Detection could be.could be.

………………new models of medical practice new models of medical practice are evolving, with increasing are evolving, with increasing attention to primary care and attention to primary care and

preventative medicinepreventative medicine..GeneticsGenetics will play a central role in this will play a central role in this

new approach ………..new approach ………..

Today's medical student therefore Today's medical student therefore face the dual challenge of face the dual challenge of mastering mastering an ever complex body of knowledgean ever complex body of knowledge along with the need along with the need to develop a set to develop a set

of problem solving skillsof problem solving skills that will that will foster foster career- long learningcareer- long learning..

It has been clear thatIt has been clear that the the traditional lecture-based traditional lecture-based

medical curriculummedical curriculum is not well is not well suited to these needs, opening the suited to these needs, opening the

door todoor to new approaches to new approaches to medical educationmedical education..

The problem-based approach The problem-based approach has been the mainstay of has been the mainstay of

curriculum change at many curriculum change at many schools, including here at schools, including here at Harvard Medical School.Harvard Medical School.

Sex-linked inheritanceSex-linked inheritance

James and BrendaJames and Brenda, , who are who are both in their mid twenties, are both in their mid twenties, are referred to the genetic clinic. referred to the genetic clinic.

They are considering starting a They are considering starting a family but are concerned because family but are concerned because Brenda has a half-brotherBrenda has a half-brother, , Chars Chars

(same mother, different father),(same mother, different father),

who haswho hasDuchene's Muscular DystrophyDuchene's Muscular Dystrophy

This diagnosis was made at age 4, when This diagnosis was made at age 4, when Chares was evaluated for delayed Chares was evaluated for delayed

language development.language development.

At that time it was noted that he had At that time it was noted that he had achieved motor milestones normally in the achieved motor milestones normally in the first year of life but had difficulty climbing first year of life but had difficulty climbing stairs and was considered to be clumsy in stairs and was considered to be clumsy in

preschool.preschool.

A serum A serum creatine phospokinasecreatine phospokinase assay assay revealed a level of 11,000 mU/ml (normal revealed a level of 11,000 mU/ml (normal

< 30), and a muscle biopsy showed a < 30), and a muscle biopsy showed a pattern typical for Duchene's muscular pattern typical for Duchene's muscular

dystrophydystrophy..

Duchene's Muscular DystrophyDuchene's Muscular Dystrophy

Progressive loose of muscle strengthProgressive loose of muscle strength X-linked recessive traitX-linked recessive trait Occurs mostly in malesOccurs mostly in males Gower’s signGower’s sign Gradually ParalyzedGradually Paralyzed Late cardiomyopathy Late cardiomyopathy Cardiac failureCardiac failure Death in before twentiesDeath in before twenties

Creatine Phosphokinase (CPK)Creatine Phosphokinase (CPK)

Increased levels of serum CPK even Increased levels of serum CPK even at birthat birth

Not a definite test, muscle biopsyNot a definite test, muscle biopsy

Charles is now 18 years old. He has Charles is now 18 years old. He has been wheelchair-bound since age 11 been wheelchair-bound since age 11

and has profound weakness of all and has profound weakness of all proximal muscles.proximal muscles.

He has experienced several bouts of He has experienced several bouts of respiratory infections, the most respiratory infections, the most

recent of which required prolonged recent of which required prolonged hospitalisation. His cognitive function hospitalisation. His cognitive function

is impaired as well (IQ test) is impaired as well (IQ test)

James and Brenda are James and Brenda are concerned that they are at risk of concerned that they are at risk of having a child with DMD. Having having a child with DMD. Having read literature from the Muscular read literature from the Muscular Dystrophy Association, they are Dystrophy Association, they are

also interested in knowing also interested in knowing whether they could have a child whether they could have a child with a milder disorder, Becker’s with a milder disorder, Becker’s

dystrophydystrophy

Becker’s dystrophyBecker’s dystrophy

Same muscle group as in Same muscle group as in DMD are affectedDMD are affected

The age of onset is laterThe age of onset is later The rate of progression is The rate of progression is

slowerslower

Further investigation of the family Further investigation of the family history reveals that Brenda’s history reveals that Brenda’s

mother had a brother who also mother had a brother who also received diagnosis of DMD.received diagnosis of DMD.

He had died at age of 17 of He had died at age of 17 of pneumonia.pneumonia.

Brenda’s mother has a healthy Brenda’s mother has a healthy brother as well.brother as well.

No other family members are known No other family members are known to have muscle disease.to have muscle disease.

Write done your answer Write done your answer to James and Brenda to James and Brenda

concernconcern NowNow

DystrophinDystrophin

Maintaining the structural integrity of Maintaining the structural integrity of muscle cellsmuscle cells

DMD gene was isolated in 1986DMD gene was isolated in 1986 Is about 2.3 million base pairs of DNA Is about 2.3 million base pairs of DNA

(largest known human gene)(largest known human gene) Contains at least 79 exons that Contains at least 79 exons that

produce a 14kb mRNAproduce a 14kb mRNA

Sex linked traitsSex linked traits In addition to determining gender, X and In addition to determining gender, X and

Y chromosomes have different genes Y chromosomes have different genes that have nothing to do with sexthat have nothing to do with sex

X-linked genes are on the X chromosomeX-linked genes are on the X chromosome

Y-linked genes are on the YY-linked genes are on the Y chromosomechromosome

This results in different patterns of This results in different patterns of inheritance in females and malesinheritance in females and males

X-chromosomes are larger, they have X-chromosomes are larger, they have more genesmore genes

Examples of Examples of X-linked traits – genes on the XX-linked traits – genes on the X chromosomechromosome

Red-green colorblindnessRed-green colorblindnessَEَE(8% Caucasian males)(8% Caucasian males)

HemophiliaHemophilia(blood does not clot)(blood does not clot)

Duchenne's muscular dystrophy Duchenne's muscular dystrophy (muscle weakness, early death)(muscle weakness, early death)

The eggs of the mother will contain either a normal X The eggs of the mother will contain either a normal X chromosome or an X chromosome with the mutation chromosome or an X chromosome with the mutation

causing red-green color blindness. causing red-green color blindness.

The sperm of the father will contain either the normal X The sperm of the father will contain either the normal X

chromosome or the Y chromosome.chromosome or the Y chromosome.

None of the None of the female female children would children would be red-green be red-green color blind, but color blind, but half would be half would be "carriers." "carriers."

Half of the Half of the sons would sons would inherit the inherit the allele from allele from their mother their mother and be and be

afflicted.afflicted.

X inactivationX inactivation

Mary Lyon (early 1960s) hypothesis on Mary Lyon (early 1960s) hypothesis on inactivation of one of the X chromosomes inactivation of one of the X chromosomes (dosage compensation) (dosage compensation) EG. In Mice and Calico catEG. In Mice and Calico cat

X inactivation is randomly determined but X inactivation is randomly determined but fixed and incompleatfixed and incompleat

Females Females mosaics for X chromosome mosaics for X chromosome Males Males hemizygous for X chromosome hemizygous for X chromosome

Evidence for X inactivationEvidence for X inactivation

Evidence for X inactivation

X inactivation MechanismX inactivation Mechanism There is at least 1 gene (XIST) in X There is at least 1 gene (XIST) in X

inactivation center (Xic) of the X inactivation center (Xic) of the X chromosomechromosome

It produces an mRNA of 15 to 17kb that It produces an mRNA of 15 to 17kb that coats the inactive chromosomecoats the inactive chromosome

Methylation also play an important role Methylation also play an important role in X inactivation (GC dinucleotide in X inactivation (GC dinucleotide repeats)repeats)

Questions for Sex linked Questions for Sex linked inheritance subjectinheritance subject

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

2- Calculate recurrence risk for:2- Calculate recurrence risk for: A) Heterozygous female × normal maleA) Heterozygous female × normal male B) Affected male × normal femaleB) Affected male × normal female

Sons Daughters

Affected ? % ? %

Heterozygous carrier ? % ? %

Unaffected ? % ? %

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

• A. A. 100% 100% • B. B. 75% 75% • C. C. 50% 50% • D. D. 25% 25% • E. E. 0% 0%

Fragile X syndrome Fragile X syndrome (CGG Repeats)(CGG Repeats)