Abstract
BackgroundPeriodic catatonia is a familial subtype of schizophrenia characterized by hyperkinetic and akinetic episodes, followed by a catatonic residual syndrome. The phenotype has been evaluated in two independent genome-wide linkage scans with evidence for a major locus on chromosome 15q15, and a second independent locus on chromosome 22qtel.MethodsIn the positional and brain-expressed candidate genes KIAA0767 and KIAA1646, we searched for variants in the complete exons and adjacent splice-junctions as well as in parts of the 5'- and 3'-untranslated regions by means of a systematic mutation screening in individuals from chromosome 22q-linked pedigrees.ResultsThe mutation scan revealed 24 single nucleotide polymorphisms, among them two rare codon variants (KIAA0767: S159I; KIAA1646: V338G). However, both were neither found segregating with the disease in the respective pedigree nor found at a significant frequency in a case-control association sample.ConclusionStarting from linkage signals at chromosome22qtel in periodic catatonia, we screened two positional brain-expressed candidate genes for genetic variation. Our study excludes genetic variations in the coding and putative promoter regions of KIAA0767 and KIAA1646 as causative factors for periodic catatonia.
Highlights
Periodic catatonia is a familial subtype of schizophrenia characterized by hyperkinetic and akinetic episodes, followed by a catatonic residual syndrome
A systematic mutation screening in 140 index cases with periodic catatonia and five cases with MLC detected a high degree of sequence diversity of MLC1 with evidence for further allelic heterogeneity of MLC1 mutations in MLC, but the study failed to validate an association of schizophrenia to genetic variants of MLC1
Among periodic catatonia index cases, the mutation scan revealed 15 different single nucleotide polymorphisms, among them three coding variants: two of them were observed in controls at a significant frequency, and the L309M variant, that was previously supposed to be the causative factor for chromosome 22qtel linked periodic catatonia, was found non-segregating in a further multiplex pedigree [6]
Summary
We selected two affected individuals (933, 1045) from different branches of F20, and two cases (727, 857) of smaller pedigrees F15 and F17, which were compatible with linkage to chromosome 22q [19], as well as DNA of a healthy individual as control. In the association study we included 115 unrelated cases with periodic catatonia (66 males; mean age first hospitalisation: 26.2 years, SD 10.5; age at assessment: 44.6 years, SD 17.1) and 110 blood donors as controls (60 males; mean age at assessment: 29.5 years, SD 9.4). Primers covered in overlapping fragments parts of the 5'UTR containing putative promoter regions [20] and were allocated in intronic regions to encompass the complete exon and adjacent splice-junctions as well as parts of the 3'-UTR up to ~1.0 kb. PCR products were purified by solid phase extraction and bidirectionally sequenced with ABI PRISM 3100 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA) followed by computer-assisted analyses. For restriction fragment analyses (RFLP) PCR products were amplified on a Thermocycler (Biometra, Göttingen), and subsequently digested with the appropriate enzyme (CERK V338G: DraIII; KIAA0767 S159I: MboI). Fragments were resolved on a 10% PAA gel containing 1.0 × TBE at 15 V/cm followed by silverstaining
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