Genetics of CCM

Douglas A. Marchuk, PhD Tracey P. Leedom, MS Duke University Medical Center

Duke University Chapel – the

second

most famous building on campus

Duke University Medical Center and Hospitals

Human Chromosomes - The home of the human genome

The Human Genome contains 6 billion “bits” of information.

4 “letters” of DNA Nucleotides A,C,G,T Goals 1. To determine the sequence of DNA 2. To interpret the sequence

23 pairs of chromosomes per cell 22 autosomes (chromosomes 1-22) Plus the sex chromosomes XX = females, XY = males

DNA=The Double Helix

D

eoxyribo

n

ucleic

A

cid Each chromosome is highly compacted in the cell.

Each cell contains the entire amount of genetic information

The sequence of letters (nucleotides) determines the code for the genes How many genes?

Old estimates before HGP = 100,000 With the almost complete sequence Celera says 30,000 Public effort says 30,000

But, the lists are not the same!

Question: If all cells have the same DNA information, why do they (the cells) look and act differently?

Each gene (

DNA

) is coped into a message (

RNA

) to instruct the cell to make a specific

Protein

. (The Central Dogma of Molecular Biology) Each type of cell (bone, blood vessel, brain etc) is instructed to make a

different set

of proteins required for the functions of that cell type.

Question: How does a genetic mutation cause an inherited disease?

A mistake (mutation) in the DNA code will instruct the cell to make an altered (faulty) protein. The faulty protein cannot perform its task.

An inherited mutation will make a faulty protein in every cell where that protein is normally found. This will affect those parts of the body that contain the cells that make the faulty protein.

Autosomal Dominant means a 50% chance of passing the faulty gene to your offspring. Both sons and daughters are at risk.

Autosomal Dominant means that even one faulty copy of a gene is sufficient to cause a problem - resulting in disease

Genetics of CCM

• Can be sporadic or familial • If familial, inheritance is autosomal dominant • Some families may have the familial form and not know it because only one person shows symptoms

Incomplete Penetrance

• Not everyone with a genetic mutation will develop symptoms or show lesions on MRI • One study suggested that up to 75% of families with the “sporadic” form actually have the familial form when screened by MRI • MRI on first-degree relatives of anyone with CCM is very important • Genetic testing is the only way to be sure

C n n n C n n n C n n n

Gene Name

CCM1 CCM2 CCM3

Chromosome Location

7q21

Protein Name

KRIT1 7p13 Malcavernin 3q25.2-q27 Unknown

Screening for CCM

• Done by MRI – Expensive, difficult for children • Hope is to develop clinical genetic test – Would allow diagnosis from blood instead of MRI – MRI could then be used to monitor those with a known gene mutation

Presymptomatic Test Reproductive Decisions Diagnostic Test Population Screen

Research or Clinical Testing?

• Research – Usually no cost to participant – May take a long time – Usually no written results given – Mutations must be confirmed in a clinical laboratory • Clinical – Usually a “fee for service” test – Usually takes less time than research testing – Will get some form of written results – Decisions may be made based on these results

Which Gene?

• CCM1 – Gene location is known, DNA sequencing can be done • CCM2 – Gene location is known, DNA sequencing can be done • CCM3 – Gene location is unknown – Once the gene is located, DNA sequencing will be available

GCTTACGATAAGGCTA GCTTACGATAAGGCTA

Gene Protein

GCTTACGATAAGGCTA

Typical protein

GCTTACAGGCTA

Altered protein

No test is perfect, especially one based on DNA sequencing. Complex technical issues can cloud the interpretation of the test.

Therapy for Genetic Disorders often lags behind Gene Testing It is much easier to identify a mutation in a gene than to cure or treat the mutant gene or protein.

Genetic Testing comes with some built-in concerns

Each person must weigh the benefits and consequences of testing.

Consequences for both the person and his/her family.

Genetic counselors can help interpret test results and make informed decisions about health care, family issues and other personal concerns.

Genetic Testing requires protections against breeches of confidentiality.

Greetings from the Marchuk laboratory