The metabotropic glutamate receptor 8 gene at 7q31: partial duplication and possible association with autism
- 1Department of Pediatrics, Wayne State University, Detroit, MI 48201, USA
- 2Department of Neurology, Wayne State University, Detroit, MI 48201, USA
- Correspondence to: Dr A H M Mahbubul Huq, Division of Neurology, Children’s Hospital of Michigan, 3901 Beaubien Blvd., Detroit, MI 48201, USA;
Family and twin studies have shown a high monozygotic to dizygotic twin risk ratio in autistic disorder and a sib relative risk between 50 to 100, suggesting that the predisposition to develop autism is largely genetically determined.1,2 The family, twin, and linkage data suggest that inheritance of autism is complex, and multiple genes interacting in variable combinations in additive, multiplicative, epistatic, or as yet unknown fashions are involved.
There is strong support for a role of the chromosome 7q21–34 region in the aetiology of both autism and language disorders.3 Several whole genome screens have found some evidence of excess allele sharing in an overlapping 60 cM region of 7q21–34 in autism.4–9FOXP2, a gene on 7q31, is mutated in a severe form of speech and language impairment segregating within a single large pedigree, but a recent study found no association with autism.10 A recent report has found nominally significant association of the WNT2 gene at 7q31 with autism but a subsequent study has reported no association.11,12 A recent study has suggested that the reelin gene at 7q22 may be one of the loci contributing to positive linkage between chromosome 7 and autistic disorder, but most likely not the major one.13
The 7q31 region contains the GRM8 gene, a good positional and functional candidate for susceptibility to autism. Based upon animal model, neurochemical, and neuropharmacological studies, autism has been proposed to be a hypoglutamatergic disorder.14 There is a report of alterations in the glutamate neurotransmitter system in postmortem brains of autistic subjects.15 A form of protein synthesis dependent synaptic plasticity, long term depression, which is triggered by activation of metabotropic glutamate receptors, is selectively enhanced in the hippocampus of mutant mice lacking FMRP.12 Given that many fragile …