Novel mutations consolidateKCTD7as a progressive myoclonus epilepsy gene
| Autor: | Hannu Kalimo, Angela Schulz, Maria Kousi, Liisa Myllykangas, Anna-Elina Lehesjoki, Erik Riesch, Aarno Palotie, Füsun Alehan, Stella Calafato, Verneri Anttila, Outi Kopra, Johannes R Lemke, Eveliina Jakkula, Michael Alber, Meral Topçu, Sarenur Gökben |
|---|---|
| Přispěvatelé: | Çocuk Sağlığı ve Hastalıkları |
| Rok vydání: | 2012 |
| Předmět: |
Potassium Channels
Ataxia Turkey KCTD7 Blotting Western Intracellular Space Single-nucleotide polymorphism Progressive myoclonus epilepsy Biology Polymorphism Single Nucleotide Article Mice 03 medical and health sciences 0302 clinical medicine Genetics medicine Animals Humans Missense mutation Cells Cultured Genetics (clinical) 030304 developmental biology Brain Chemistry Genetics & Heredity 0303 health sciences Genetic heterogeneity Homozygote Chromosome Mapping Sequence Analysis DNA Myoclonic Epilepsies Progressive medicine.disease Disease gene identification Pedigree 3. Good health Phenotype Microscopy Fluorescence Mutation medicine.symptom Myoclonus 030217 neurology & neurosurgery |
| Zdroj: | Journal of Medical Genetics. 49:391-399 |
| ISSN: | 1468-6244 0022-2593 |
| DOI: | 10.1136/jmedgenet-2012-100859 |
| Popis: | Background The progressive myoclonus epilepsies (PMEs) comprise a group of clinically and genetically heterogeneous disorders characterised by myoclonus, epilepsy, and neurological deterioration. This study aimed to identify the underlying gene(s) in childhood onset PME patients with unknown molecular genetic background. Methods Homozygosity mapping was applied on genome-wide single nucleotide polymorphism data of 18 Turkish patients. The potassium channel tetramerisation domain-containing 7 ( KCTD7 ) gene, previously associated with PME in a single inbred family, was screened for mutations. The spatiotemporal expression of KCTD7 was assessed in cellular cultures and mouse brain tissue. Results Overlapping homozygosity in 8/18 patients defined a 1.5 Mb segment on 7q11.21 as the major candidate locus. Screening of the positional candidate gene KCTD7 revealed homozygous missense mutations in two of the eight cases. Screening of KCTD7 in a further 132 PME patients revealed four additional mutations (two missense, one in-frame deletion, and one frameshift-causing) in five families. Eight patients presented with myoclonus and epilepsy and one with ataxia, the mean age of onset being 19 months. Within 2 years after onset, progressive loss of mental and motor skills ensued leading to severe dementia and motor handicap. KCTD7 showed cytosolic localisation and predominant neuronal expression, with widespread expression throughout the brain. None of three polypeptides carrying patient missense mutations affected the subcellular distribution of KCTD7. Discussion These data confirm the causality of KCTD7 defects in PME, and imply that KCTD7 mutation screening should be considered in PME patients with onset around 2 years of age followed by rapid mental and motor deterioration. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|