RESUMEN
BACKGROUND: Periodic 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. METHODS: In 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. RESULTS: The 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. CONCLUSION: Starting 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.
Asunto(s)
Cromosomas Humanos Par 15/genética , Cromosomas Humanos Par 22/genética , Análisis Mutacional de ADN , Proteínas Mitocondriales/genética , Esquizofrenia Catatónica/genética , Estudios de Casos y Controles , Codón/genética , Exones/genética , Familia , Predisposición Genética a la Enfermedad , Variación Genética , Humanos , Linaje , Fenotipo , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas/genética , Esquizofrenia Catatónica/clasificaciónRESUMEN
The aim of the study is to validate the etiological role of KIAA0027/MLC1 in childhood-onset megalencephalic leukoencephalopathy with subcortical cysts (MLC) and in schizophrenia, particularly the catatonic subtype, which were reported to be allelic diseases. Among a series of five patients with MLC, four mutant alleles were detected: one case of compound heterozygosity for a splice site mutation and a six-base-pair in-frame deletion, one patient with a homozygous frameshifting insertion-deletion, and a further case heterozygous for a A157E substitution. A systematic mutation screening in 140 index cases with schizophrenia revealed 13 different single nucleotide polymorphisms (SNPs): one SNP in the 5'-UTR, seven SNPs in intronic regions, two synonymous codon variants (T52, Y199), and three coding variants. Two of them, C171F and N218K, were observed in controls at a significant frequency. The L309M variant that was previously supposed to be the causative factor for chromosome 22q(tel) linked-periodic catatonia was found nonsegregating in a further multiplex pedigree. Furthermore, a complicated 33-bp insertion/deletion polymorphism at the 5'-end of exon 11 of MLC1 was found at equal frequency among schizophrenic patients and controls. In summary, our study provides further evidence for allelic heterogeneity in megalencephalic leukoencephalopathy, excludes MLC1 as a susceptibility locus for schizophrenia, and thereby rules out that MLC and schizophrenia are allelic disorders.