I've done so in previous posts e.g. this one or this one.
Which is why a new paper is important. The authors, a large Turkish-American collaboration, found that mutations in a gene, WDR62, are associated with severe brain malformations in 9 patients. But what's interesting is that it doesn't cause any particular malformation.
If you have two faulty copies of this gene, your brain won't be normal, but what goes wrong varies widely amongst different people. Although the 9 cases had some features in common, such as microcephaly (small head and brain), in other respects they differed greatly.
As the authors put it, mutations in WDR62 cause
a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients... had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities.These are distinct entities, in the sense that you can have any one of them, without having the others. And they are different brain changes. What the authors mean is that everyone assumed that, because they're different, they must have different genetic causes. They've just shown that this is wrong.
So what is WDR62 "for"? Experiments in mice showed it to be involved in the migration of new neurons from their origin to their final location in the brain. So it's "for" correct neuronal placement, although how it works remains unclear.
WDR62 ought to remind us that there's a long and winding road from gene to phenotype, and that the same gene can, when mutated, cause very different symptoms. This is especially interesting in the light of recent evidence showing that the same mutations can cause a range of behavioural disorders from autism to ADHD to schizophrenia.
Bilgüvar K, et al (2010). Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature, 467 (7312), 207-10 PMID: 20729831
2 comments:
This is a good reminder that the phenotype is what we get at the end of your winding road. One reason for variable expressions of major mutations is genetic interaction. There is, for instance, a familial type of Creutzfeldt-Jakob disease associated with a point mutation on codon 178 of the prion protein gene on chromosome 20. This is a diffuse spongiform encephalopathy that presents with subacute dementia – if a common allelic polymorphism at codon 129 on the same gene codes for valine, which it does 38% of the time. However, if the polymorphism at codon 129 codes for methionine then the clinical phenotype is very different – the same point mutation at codon 178 then presents as fatal familial insomnia with subacute intractable insomnia, dysautonomia, and destruction of thalamic nuclei. Thus a common allelic polymorphism separate from the major mutation can radically alter the clinical expression of the major mutation. It is not unreasonable to conjecture that similar genetic interactions may be in play for some major psychiatric disorders that show variability in pedigrees – schizophrenia, schizo-affective, and bipolar disorders, for instance. Another case may be recurrent familial unipolar depression and bipolar disorder.
Here is the PubMed ID for this 1992 report by LG Goldfarb et al in Science: PMID:1439789
Couldn't these phenotypes be explained by expression timing during fetal development?
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