Our research projects on Periodic Catatonia are currently focused on the investigation of two genetic loci, SLC12A6 and MLC1.
Potassium-chloride co-transporter 3 (SLC12A6, KCC3)
Recessive mutations of the potassium-chloride cotransporter 3 gene (SLC12A6, KCC3) cause severe peripheral neuropathy frequently associated with agenesis of the corpus callosum and psychoses (ACCPN, OMIM 218000). SLC12A6 is localized on chromosome 15q14, a region that has previously been shown to contain susceptibility genes for both bipolar disorder and chromosome 15-related schizophrenia (SCZD10). Mutation analysis of SLC12A6 was carried out by direct sequencing of PCR-generated DNA fragments in 2 affected members of a multiplex family, and 3 non-affected individuals. A case-control study was performed to assess association of variants with bipolar disorder and schizophrenia in a large sample. Several variants, including two rare single nucleotide polymorphisms (G/A, G/A) in the promoter and 5'-UTR, and a thymidine insertion in intron 4 were found (Meyer et al. 2005). The two G-variants and the insertion variant were co-inherited with SCZD10 in a large family that strongly supports the region on chromosome 15q14-15 between markers D15S144 and D15S132. Furthermore, they are in linkage disequilibrium with each other, and significantly associated with bipolar disorder in a case-control study. These variants are functional due to epigenetic alteration.
MLC1 spans approximately 24 kb of genomic DNA. The protein consists of 377 amino acids, with a molecular weight of 41 kDa and eight predicted transmembrane domains. The N- and the C-termini are located intracellularly. It is notably expressed in distal glial processes (Boor et al., 2005). So far, functional data are lacking. Leegwater et al. (2002) elucidated via mutation analysis that the transmembrane protein MLC1 causes a disease designated as megalencephalic leukoencephalopathy with subcortical cysts (MLC, OMIM #604004). MLC is an autosomal recessive disorder characterized clinically by macrocephaly and deterioration in motor functions, cerebellar ataxia and mental decline (Van der Knaap, 1995). We demonstrated in 2001 that a certain missense mutation in MLC1 cosegregates with periodic catatonia in an extended pedigree. In a further mutation analysis this specific mutation variant was found in a single patient (Rubie et al., 2002).
References on the project:
Moser D., Ekawardhani S., Kumsta R., Palmason H., Bock C., Athanassaidou Z., Lesch K.P. and Meyer J. (2008): Functional analysis of a potassium-chloride co-transporter 3 (SLC12A6) promoter polymorphism leading to an additional methylation site. Neuropsychopharmacology: doi:10.1038/npp.2008.77
Meyer J, Johannssen K, Freitag CM, Schraut K, Teuber I, Hahner A, Mainhardt C, Mossner R, Volz HP, Wienker TF and others (2005): Rare variants of the gene encoding the potassium chloride co-transporter 3 are associated with bipolar disorder. Int J Neuropsychopharmacol 8(4):495-504.
J. Meyer, K. Schraut, G. Ortega, F. Rüschendorf, G. Nürnberg, G. Stöber, R. Mössner, K. Saar, T. F. Wienker, A. Reis, K. P. Lesch (2002): The potassium-chloride cotransporter 3 gene (KCC3) is excluded from a newly defined 10.9 centiMorgan candidate region for chromosome 15 related schizophrenia (SCZD10). Eur. J. Hum. Genet. 10 (Suppl. 1): 80.
J. Meyer, K. Schraut, K. Johannssen, G. Ortega, A. Reif, K. P. Lesch
(2002): Positional cloning of schizophrenia-related genes on chromosome 15q14-15. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 114, 860
J. Meyer, K. Johannssen, C. M. Freitag, K. Schraut, Z. Athanassiadou, I. Teuber, A. Hahner, R. Mössner, D. McKeane, DA Stephan, A. Reif, KP Lesch (2003): Variants of the gene encoding the potassium-chloride cotransporter 3, a positional candidate on chromosome 15q14, are associated with psychoses of the schizophrenic and bipolar spectrum. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 122B, 34.
Lindenberger, B. (2003) Untersuchung einer seltenen und mit Psychosen assoziierten Promotorvariante des Kaliumchlorid-Kotransportergens (KCC3/SLC12A6) hinsichtlich potentieller Methylierung. Diploma Thesis.