How Genetics is Changing the Game in Ataxia. Margit Burmeister, PhD University of Michigan

How Genetics is Changing the Game in Ataxia Margit Burmeister, PhD University of Michigan 1 Disclaimer  The information provided by speakers in a...
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How Genetics is Changing the Game in Ataxia Margit Burmeister, PhD University of Michigan

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Disclaimer 

The information provided by speakers in any presentation made as part of the 2013 NAF Annual Membership Meeting is for informational use only.



NAF encourages all attendees to consult with their primary care provider, neurologist, or other health care provider about any advice, exercise, therapies, medication, treatment, nutritional supplement, or regimen that may have been mentioned as part of any presentation.



Products or services mentioned during these presentations does not imply endorsement by NAF.

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Disclosure 

The following personal financial relationships with commercial interests relevant to this presentation existed during the past 12 months:



No relationships to disclose

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Geneticists’ “symbols” Circle = female

Square = male

Filled circle or square = affected with ataxia Deceasedp erson couple (married… or not) child of the couple 4

Genetic forms of ataxia 

Dominant Form: Inherited through families

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Genetic forms of ataxia: 





Dominant with incomplete penetrance

Some family members may not become ill although they carry the disease gene Older generation may be less severe 6

Dominant ataxias 







Most people with dominantly inherited forms of ataxia have mutations in a known gene A genetic blood test can find mutations in the genes causing SCA1, SCA2, SCA3 or SCA6 Some people with dominant ataxias have mutations in other genes – also can be tested Some people with dominant ataxia have no mutations in any of the known genes

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Genetic forms of ataxia: 

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Recessive inheritance

Parents are not affected Parents may be related May be an isolated case or siblings 8

Recessive forms of ataxia: 



Most but not all recessive forms of ataxia have onset in childhood Most common recessive form is Friedreich’s Ataxia  genetic

 

blood test can confirm the diagnosis

There are many other recessive ataxias Most people who don’t have Friedreich’s Ataxia test negative for mutations in known ataxia genes

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Ataxia Genetic Research: Families Each family that we study carries mutations in a different gene

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Finding genes in the 21st Century 

1) Recruit families negative for known ataxia genes  Affected and unaffected members 

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2) cell lines from blood 3) DNA from blood 4) Sequence all 20,000 genes (“exomes”) from two affected individuals

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Success Stories Two Examples how we Identified New Ataxia Genes

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Turkish Consanguineous Family  



Children with ataxia from birth Also suffer from mental retardation and delay Parents are first cousins

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Next, we sequenced all 20,000 genes from blood samples of these two children This whole exome sequencing by next generation sequencing has only recently become possible

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Whole Exome Sequencing of Two Affected individuals 6271 new and mutations 3999 novelfound variants 6271 and 3999 in each case

713 found in both homozygous

3 potentially 2 mutations in genes known damaging to have other characteristics

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CWF19L1 – novel gene 15

CWF19L1 function is lower    

The new gene also works in blood We test the cell lines of the 2 children Compare to other ataxias and controls The gene functions less well in the two cell lines with mutations than in other cell lines

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Zebrafish Model of Ataxia 

Zebrafish have the same genes as humans



Zebrafish can be easily manipulated



Genetic engineering used to put the same mutation that we found in the children into zebrafish

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CWF19L1 mutation leads to movement disorder in zebrafish CWF19L1 mutant zebrafish

normal zebrafish

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Second Success Story

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Dominant Ataxia 

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Dominant, Ashkenazi Jewish family with adult onset ataxia Exome sequencing Mutation in the same gene as reported NAF 2012 by Dutch group

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Dominant Ataxia 

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Dominant, Ashkenazi Jewish family with adult onset ataxia Exome sequencing Mutation in the same gene as reported NAF 2012 by Dutch group Also in a Taiwanese family – collaboration Several French, several Japanese families

Annals of Neurology. 2012 (collaboration with Taiwan, France and Japan) 21

KCND3 Mutations in SCA19 

KCND3 is a Potassium Channel Gene



Potassium Channels are important in nerve function



Mutations in other Potassium Channel genes cause Episodic Ataxias

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KCND3 mutations are common 

Mutations in KCND3 were so far seen in at least 10 families all over the world – one in the US



Some were single cases without family history



Incomplete penetrance – may appear sporadic



All families show less severe ataxia in the older generations compared to the youngest ones

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Using Results in practice Several adults who are not (yet?) affected have undergone clinical genetic testing to determine their own risk A drug used for epilepsy might be beneficial in this case – currently being tried by some of the family members 24

Conclusion Exome Sequencing and other New Techniques makes it possible to find new Ataxia Genes quickly Can be used to help with diagnosis Hope knowing genes may also help in finding new treatment 25

Thinking Exome sequencing 



When sequencing a person’s exome, we may also find out information about your risk of other diseases like breast cancer or Alzheimer’s or heart disease  Would you want to know?  What if nothing can be done about the problem? Some people now pay a company to have their own exome sequenced.  Doctors don’t understand the results  Could patients misunderstand them? 26

Acknowledgment 

Participating Families



Randi Burns James Dowling Jun Z. Li Karen Majczenko Henry Paulson Erin Sandford Vikram Shakkottai Jishu Xu

      

Poster by Dr. Erin Sandford if you are interested in participating in our research.

Funded by National Institute of Health Neurological Disorders and Stroke 27

New Trends in Medicine?

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iPSC: Induced Pluripotent Stem Cells (e.g. fibroblasts from patients and controls)

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iPS or iN from fibroblasts  

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Invited family to come to Ann Arbor One affected, spouse and (obligatory heterozygote) carrier underwent skin biopsy (minor surgery) to donate fibroblasts Fibroblasts converted to iPS 4-6 weeks later differentiated into into neuron-like cells 2011: 2 publications show how to directly convert from fibroblasts to neuronal cells

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Patient-specific iPS cells for neurological disorders Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons

Dimos, et al., Science 321: 1218, 2008 31