The blog post titled ‘The genetic lottery’ came about as a result of my attempt to understand the link between Ruzbeh’s mutation and the severity of his symptoms. His mutation being a missense mutation (one where just one amino acid in the protein coded for by the gene, gets replaced by another), is generally considered less harmful/severe than let’s say, a deletion. At least by laypeople, which is what I am.
Now here is some feedback from a regular reader (my dear husband) about that post:
I didn’t understand a thing!
What on earth was that all about?
That was not a blog post; that was a white paper on Norrie disease!
Right… Um…. Well… Yes…. :-))))
Yet another reader (from the Norrie support group) was left feeling confused, not only with respect to the contents of the post, but also its title.
So here is another shot at it – simpler, shorter, and trying to address the above mentioned concerns.
For fear of writing yet another mile long post, I am going to split it into two – an explanation of the title in today’s post, and that of the content in the sequel to this post.
So here we go again.
(a) My use of the phrase ‘genetic lottery’ referred to the fact that some of those born with Norrie Disease (ND) have it worse than others. These are the 30-50% of cases who manifest neurological problems in addition to the other symptoms of the disorder. A double whammy, if you like.
We might well ask, why only 30-50%, why not 100%? There is, as yet, no answer to this question. My hypothesis is, that this has to do with the severity of the mutation. Not that I’m an expert of anything; I’m not. Most scientists on the other hand, tend to point the finger to ‘other genes’. Since the functioning of the brain is a puzzle yet to be solved, we could attribute the mental deficit associated with ND to ‘other genes’. I’m just not sure how we could explain the high figure of 30-50% when the incidence of autism in the general population is pegged at between 1% and 2% (depending on which report you happen to be reading).
While it is my belief that there is a definite link between severity of mutation and severity of symptoms, one must keep one’s mind open to the possibility of modifier genes making the outcome of an already severe mutation even worse. As the name suggests, modifier genes are genes which modify the clinical outcome of another gene. Click here to see how modifier genes modify the outcome of mutations of a gene called CFTR. Research is needed to identify the modifier genes for ND.
So, if we were to suppose that there is a link between the severity of the mutation and the severity of symptoms, then it begs the question - which mutations of NDP (the Norrie disease gene) are more severe than others? This is exactly the question I was trying to address in ‘The genetic lottery’, and I hope to explain it more clearly in the sequel to this post.
(b) Another meaning of the phrase ‘genetic lottery’ could have been (but in my blog post, was not), the fact that some people are born with ND at all. It is after all, a rare disease. Just how rare? There is no official estimate of the number of cases worldwide. The orphanet description for ND mentions that there are 400 published cases to date, which is neither here nor there. It tells us nothing about the incidence or the prevalence of the disorder.
(c) Yet another meaning of the phrase ‘genetic lottery’ could have been (but in my blog post, was not) the fact that some disease causing mutations of the gene NDP do not result in ND. Instead they might lead to such lovelies as Coat’s disease, ROP (retinopathy of prematurity) stages 4b & 5, FEVR (familial exudative vitreoretinopathy), and PHPV (persistent hyperplastic primary vitreous). None of these other diseases is as severe as ND. An estimated 77% of mutations of NDP result in ND.
Here we might well ask – how on earth is it possible that mutations of one gene result in several diseases? While searching for an answer to this question, I came across an article which explains how different mutations of a gene called SHANK1 lead to two distinct disorders – autism in one case and schizophrenia in the other. A study was conducted to try and find the reason why different mutations of SHANK1 resulted in two distinct psychiatric disorders. The result of this study? The mutation which led to autism (deemed to be the more severe of the two disorders) resulted in a complete loss of gene product (i.e. the protein coded for by the gene) whereas the mutation which caused schizophrenia resulted in a truncated product (the resulting protein was about half the size). In other words, the severe mutation led to a severe outcome whereas a less severe mutation led to a less severe outcome. Might this explain why different mutations of the gene NDP result in different diseases? Perhaps. It could also be the case that in addition to the type of mutation, modifier genes (see (a) above) also contribute to mutations of the same gene resulting in different diseases.
(d) And finally, here is yet another interpretation of the phrase ‘genetic lottery’. There are cases where the same mutation of the gene NDP has resulted in different outcomes/symptoms. At times this has been the case even within the same family. According to scientists, the answer lies in – you guessed it - modifier genes (see (a) above).
I hope things are a lot clearer this time round, and I’m off to write part II of this post.
Till next time then,
Meenu.