Thursday, June 3, 2010

Schizophenia, autism, genes....(2)

I will briefly summarize a recent PNAS paper dealing with the possible involvement of a rare disease allele in the causation of a common disease, schizophrenia.

De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia.
Gauthier J, Champagne N, Lafrenière RG, Xiong L, Spiegelman D, Brustein E, et al
Proc Natl Acad Sci U S A. 2010 Apr 27;107(17):7863-8

Hypothesis: a “significant” fraction of schizophrenia cases are due to new mutations. This hypothesis derives from 1) a reported association between paternal age and schizophrenia 2) constant 1% schizophrenia incidence in various populations despite decreased reproductive fitness 3) report of increased de novo CNV rate in schizophrenia. Note that there are alternate explanations for the first two scenarios, for instance, since schizophrenia is a spectrum disorder the relevant genes may be propagated by individuals with schizotypal or schizoid personality disorders, rather than schizophrenics; secondarily, these individuals may marry or have children later due to their behavioral peculiarities.

This paper reports on screening of one of many rare genetic causes of autism, the SHANK3 gene, in a large (185 probands) cohort of individuals ascertained for schizophrenia. 6 nonsynonymous variants were found only in the schizophrenia cohort, and 4 (H494Q, S952T, G1011V, and P1134H) were transmitted from an unaffected parent and excluded from further analysis. This quoted comment "Therefore, these four transmitted nonsynonymous variants can be excluded from a direct role as dominant mutations in SCZ," is not necessarily accurate from a genetics standpoint, as dominant mutations may show incomplete penetrance or variable expressivity, etc. The authors appear to be assuming that penetrance of a dominant disease gene must be high. In any case, two cases had de novo mutations not found in 285 controls. One of these individuals had two affected brothers with the same mutation, likely due to paternal gonadal mosaicism. All individuals had premorbid MR. It seems that this gene may be responsible for mental retardation primarily, with associated behavioral phenotypes such as autistic behaviors and nonspecific psychosis. I think its unlikely to account for schizophrenia in the healthy premorbid population, i.e., it is unlikely to be a schizophrenia-specific gene. Note that classical schizophrenia is characterized by usually normal premorbid development, with a later psychotic break (think John Forbes Nash).

The authors do some interesting neurobiological assays that show that one of the mutations (nonsense mutation found in the three brothers) fails to promote somatic sprouting of neurites compared with control neurons, while the missense mutation was not shown to affect neurite outgrowth. Note that there have been other groups who've reported lesions in genes in the same area causing neurite outgrowth defects and schizophrenia (e.g, Budel et al, J Neurosci. 2008 Dec 3;28(49):13161-72; Genetic variants of Nogo-66 receptor with possible association to schizophrenia block myelin inhibition of axon growth....a paper which provides evidence that four human NgR1 variants from schizophrenic individuals are functionally inactive in myelin-induced growth cone collapse assay, may possess dominant negative function in vitro, and may severely disrupt NgR1 signaling in individuals bearing these variants.) Nogo-66 is in the 22q11 region. Shank 3 is in the 22q13 region and is not deleted in the 22q11 deletion syndrome.

Note that there is already a well-described 22q13 deletion syndrome (Phelan-McDermid syndrome), which is related to moderate to severe developmental delay and mental retardation. The Shank3 gene is thought to be responsible for the neurological deficits of the syndrome (Wilson et al., 2003).

MR is already though to be a lesion of dendritic and synaptic pathology in some cases, perhaps diverse schizophrenia genetic pathologies will be shown to coalesce around a final common pathway of dysfunctional neurite outgrowth......