Genetics and lifestyle

I recommend the material, available for all to read, at the American group's site. They have numerous excellent "Educational articles" and a newsletter called the "Quarterly Advocate".  I intend to refer to these materials in many of my posts, but I will analyse them and comment.
The "fall 2006" issue can be read here:

http://www.bccns.org/news/2006Fall.pdf

It included an article called "The Genetics of Gorlin Syndrome: A Primer”
Written by: Sherri J. Bale, Ph.D., FACMG, Clinical Director, GeneDx, Inc.

Readers of this blog may find it a useful way to begin to understand how this syndrome can be inherited.  In my comments on this article, I mean no disrespect to the author; it is just that there are some other things which I consider worthy of mention.

(1) This syndrome results from a malfunction in the "Sonic Hedgehog Signalling Pathway", which has more than the single component controlled by the PTCH1 gene, also called "Patched 1".  That is why it is described as a pathway.  Some cases of Gorlin Syndrome result from a mutation in one of the other steps of the pathway, such as the gene called "Smoothened" ("SMO").  At present, patients can access a genetic test for PTCH1 mutations, but not for changes in other parts of the pathway.

The severity of symptoms varies between people with GS.  Much of this variation must depend on the person's environment, especially their exposure to carcinogens, such as UV and Xrays; see point (3).  One genetic factor influencing severity of GS has been identified; some people carry a mutated PTCH2 gene, as well as a mutated PTCH1 gene, according to the section on "Etiology" in this scientific review of relevant research:

1. Nevoid basal cell carcinoma syndrome (Gorlin syndrome)
Lorenzo Lo Muzio
Orphanet Journal of Rare Diseases 2008, 3:32doi:10.1186/1750-1172-3-32
The electronic version of this article is the complete one and can be found online at: http://www.ojrd.com/content/3/1/32

It is in technical language for scientists and doctors, but it explains that carrying a mutation in one of our copies of both PTCH2 and PTCH1 leads to greater severity of GS symptoms than when only PTCH1 is mutated.  A mutation only in PTCH2 seems to have no effect in people who have 2 working copies of PTCH1.


(2) The author described the GS as: " 'inherited', or passed from one generation to another."

This is not quite accurate; see later where she refers to those of us with GS who have 2 unaffected parents.  We are "new mutants" or as she termed it, we "resulted from de novo mutation, meaning that they represent the first occurrence of a mutation of the PTCH gene in their family".  A better term for the situation is to describe GS as "heritable" = "able to be inherited".  If _you_ have GS, there is a 50% chance, each conception, that your baby will have GS..... if you choose to have children (I chose to remain childless).  If you want children, there are ways to avoid passing on GS; see a genetic counsellor.  Science IS advancing, especially in genetics, so maybe they will develop a way to screen your embryos for the GS mutation (if you are using IVF).  A man with GS might simply choose to use donor sperm to inseminate his wife.

For a list of Australian Genetic Counsellors, see my post"Brochure for patients and carers". The url:

http://gorlinsyndromeaustralia.blogspot.com/2011/08/brochure-for-patients-and-carers.html

(3) My understanding is that having a "mutated PTCH gene" is not quite like having a gene "for" GS, like having a gene "for" red hair or "for" any of the simple single - gene disorders; in GS, we have only a single copy of a very vital gene (PTCH1) which keeps a cell doing what it is supposed to do as a normal part of the body, that lives only to serve other cells of the body.  Anything that causes that single copy of the PTCH1 to stop working is likely to lead to trouble for the body.  And bad things do happen to genes, all the time; they can be broken or lost from cells as the cells multiply ... just by chance ("bad luck", you might say).  Sometimes, when all chromosomes are copied as part of cell division, the 2 copies of exactly the same chromosome end up in the same daughter cell, instead of each daughter cell getting a copy of each separate chromosome; if the 2 "dud" copies end up in one daughter cell, that cell goes on a wrong path from then on, multiplying to form a tumour, and the 2 good copies in the other daughter cell keep it acting normal, as before.  The scientific term for this is "loss of heterozygosity":

http://en.wikipedia.org/wiki/Loss_of_heterozygosity

These little errors happen all the time, as cells copy their DNA and divide; no process is perfect.  Next division, there could be the "dud" section of DNA on both chromosomes in the same cell.  That cell can no longer carry out the normal function of PTCH1, and a tumour may develop from it, as it divides.

If such a mutation happens in a cell in the testis or ovary, in cells that form gametes for the next generation, then the change might be passed to the next generation if ... a BIG "if"  ... if the altered ova or sperm happens to combine with the other partner's gamete, to form an offspring.  This is a "germline mutation" since it occurred in the cells that will form the "germ" of the next generation.

If such a mutation happens in the cells of other organs, it is called a "somatic mutation", and these cannot be passed to the next generation.  I think that the significance of "somatic mutations" is not taught about to students in schools as often as it should be, because it DOES still matter; it is thought to be a major factor in formation of tumours such as cancers. According to the "multi - hit hypothesis" of how cancers start, a cell only turns into a cancer cell after 2 or more changes in it have occurred, and we who have GS are already 1 significant step along the path that converts a normal cell into a tumour cell .... in ALL .... yes, all .... of the cells in our bodies.  But we can still slow down the rate of the other changes that occur to cells as they travel towards the state we call "malignant".  It is vital that we do so.  We have much less "leeway" to be careless with our DNA, compared to "normal" people.

What can we do to make our personal health outcome the best possible?  Try to minimise things in our environment that make these errors more likely to happen or harder for cells to repair before the next cell division happens; as far as I know, from then on, the error in part of the DNA cannot be repaired; it is copied.  Minimise exposure to carcinogens such as UV radiation and Xrays.  I reckon it is best to give up smoking, or never ever start smoking, and as far as I know, eating a diet rich in antioxidants helps our cells reduce or repair the occasional DNA damage, before it leads to longterm trouble.

To put it another way, health authorities advise everyone to minimise their risk of cancers by doing these things.  For GS people, it is very important that we take these precautions.  We still need regular checkups and must treat some tumours, but by being careful, we can minimise the number of tumours, and have a good life.