14 March 2007. Researchers based in England and Scotland have identified seven different genetic variations that are associated with schizophrenia and which all lie within or very near a single gene on chromosome 11. The gene encodes a protein called phosphohippolin, a member of the FXYD family of transmembrane proteins that modulate the activity of sodium/potassium ATPases (Na,K-ATPases). The finding, reported in the March 1 American Journal of Human Genetics online, suggests that altered Na/K homeostasis may increase susceptibility to this debilitating illness.

The region on the long arm of chromosome 11 where the researchers found the variations (11q22-24) was implicated in schizophrenia as early as 1992 (see Nanko et al., 1992). Since then, that particular snippet of the genome has come in for much scrutiny, especially one locus at 11q23 housing the gene for the D2 dopamine receptor (see SchizophreniaGene), and to a lesser extent another at 11q22 encoding the GluR4 subunit of the AMPA-type glutamate receptor (see SchizophreniaGene). Both dopaminergic (see SRF dopamine hypothesis by Anissa Abi-Dargham) and glutamatergic signaling (see SRF glutamate hypothesis by Bita Moghaddam) have been implicated in the pathology of schizophrenia.

After conducting a genome-wide linkage study, Hugh Gurling and colleagues at University College London confirmed the link between schizophrenia and chromosome 11q23-24 in 2001 (see Gurling et al., 2001). In the present study, Gurling, first author Khalid Choudhury, and colleagues at UCL; the University of Aberdeen, Scotland; and other institutes in the U.K. focused on microsatellite and single nucleotide polymorphism (SNP) markers within the region.

The researchers first looked for associations between the markers and schizophrenia in a UCL sample set comprising 496 cases and 488 controls. They found significant association for two of five randomly selected microsatellite markers. They then selected SNPs near those regions for genotyping, finding five SNPs that were significantly associated with the disease and a further two SNPs that were positively associated as part of a triple SNP haplotype. Only two of the total of seven SNPs and one of the original microsatellite markers are not located in the phosphohippolin gene, but they are located in the gene for family member FXYD2. The researchers report that these three markers show significant linkage disequilibrium with the phosphohippolin SNPs, so the FXYD2 gene may not prove to have any association with schizophrenia in and of itself.

To corroborate the findings, Choudhury and colleagues analyzed an Aberdeen sample set consisting of 858 cases and 591 controls. Two of the SNPs showed association in the Scottish samples, while combined analysis of both sample sets showed that three SNPs are still significantly associated with schizophrenia. A three SNP haplotype that was significantly associated with the disease in the UCL sample set was also associated with schizophrenia in the Aberdeen sample set. The authors write “…the fact that the same alleles and haplotypes were associated in the second Aberdeen sample suggest[s] that it is unlikely that the association between FXYD6 and SCZD is a false-positive result.”

How these SNPs may predispose to schizophrenia remains to be elucidated, but if this finding holds up in further, larger studies, the role of phosphohippolin may take on new importance. In general, though the FXYD family of proteins (named for that amino acid motif) may not be directly involved in neurotransmission, they do modulate the Na,K-ATPases that restore Na/K gradients after electrical activity. The pumps also drive transport of small molecules, including neurotransmitters, across cell membranes (see Kanner and Schuldiner, 1987) and have been implicated in neurotransmitter reuptake. Though phosphohippolin is found in neural fibers in rat brain and is most highly expressed 3 weeks after birth, it is also present in the adult brain. “This suggests that phosphohippolin may play an important role in the neuronal excitability of the CNS during postnatal development and in the adult brain,” write the authors. They suggest that the gene should now be sequenced in patients with schizophrenia to identify mutations that might affect expression or function of the protein.—Tom Fagan.

Reference:
Choudhury K, McQuillin A, Puri V, Pimm J, Datta S, Thirumalai S, Krasucki R, Lawrence J, Bass NJ, Queste D, Crombie C, Fraser G, Walker N, Nadeem H, Johnson S, Curtis D, St. Clair D, Gurling HMD. A genetic association study of chromosome 11q2-24 in two different samples implicates the FXYD6 gene, encoding phosphohippolin, in susceptibility to schizophrenia. Am. J. Hum. Genet. 2007, Mar 1. Online publication. Abstract