C4B null allele and autism

Big names in autism research was covered in one of my recent posts on this blog. At the time I did not want to name names, despite focusing on Prof. Sir Michael Rutter and his various observations on autism research and what we think we know about autism. In this post, I am going to name a name: the late Reed Warren and his various research on the C4B null allele in connection to autism.

I met Reed Warren only once, very early on in my autism research career. He was a Professor of Immunology (I think) based at Utah State University in the United States. I faintly remember that at the time of meeting him he was not in the best of health and sadly passed away not long after our meeting at a conference we were both attending. At that stage in my career, I will admit that whilst aware of his work, I did not fully understand the implications of it and how it fitted into my little corner of autism research. After doing a bit of reading around the topic over subsequent years, I now feel as though I can describe and discuss, albeit perhaps not with the same authority as Warren and his colleagues.

Here goes: what is a C4B null allele?

Well, we start at the major histocompatability complex (MHC) and its link to the immune system and its regulation. Within the genetic region occupied by the MHC, several genes for the complement proteins are found including the C4 genes which encode for the C4 protein. The C4 glycoprotein appears in two forms: C4A and C4B as a function of the C4A and C4B genes. Both versions of the C4 protein are similar in function and structure but also have some distinguishing features from each other.  The C4A and C4B genes are very polymorphic; that is there are various versions of the gene switched on or off which function to varying degrees depending on heterozygoisty or homozygosity. There is a good overview of heterozygosity here and its importance for genetic diversity; basically we all have two copies of a gene as a function of our paired chromosomes and depending on whether or not a gene is expressed the same or differently on each chromosome in that pair will describe the zygosity. It is quite possible for a person to carry what's called a null allele for the C4A and/or C4B genes, which basically means that the respective gene makes little or no C4A or C4B protein. If a person is homozygous for the null allele (the gene on both chromosomes is switched off), it means that the gene should make absolutely no protein. I know I have probably not done justice to the concept of the C4B null allele with this brief description, but as with many things related to genes, such things are never easy to interprete or explain.

The C4B null allele has cropped up a few times in the research literature in connection to things like type-1 diabetes, coeliac disease and cases of recurrent spontaneous abortion. It is perhaps with autism in mind, that most of the research has been done as witnessed by papers here, here and here. OK I hear you say, so what if a C4B null allele is present, what does it mean?

Well, this is where a degree of speculation takes over, as once again the limits of my competence are tested. It is important to realise that the presence of a C4B null allele is not exclusively tied into autism. Like many genetic findings, the relationships are complex and overlapping with other conditions and asymptomy. Warren and colleagues in their papers hinted at this in their 1991 paper, and instead suggested that the presence of a C4B null allele might lay the foundations for a genetic predisposition, compounded by other issues with the immune system and exposure to one or more pathogens. Their later paper published in 1996, whilst taking into account the relatively small participant numbers included, noted the greatest frequency of one (or both?) C4B null allele was actually found in cases of reading disorder (67.7%), followed by ADHD (56.5%) and then autism (48.9%) (controls = 20.3%). This would suggest that the C4B null allele may play a role in autism, but also in these other conditions.

Following the 'game changer' that was the results of the California Autism Twin Study, I think our view of genes and autism is undergoing a bit of a shift at the moment. Whilst being no great lover of the 'autism is totally genetic' hypothesis still being banded around by some, the C4B null allele and other genetic stories are still worthy of some consideration in some cases of autism. Indeed only very recently has the C4 gene come up again in relation to some speculations on mycobacterium paratuberculosis and autism.

In memory of Reed Warren and his contribution to autism research.