CDK19 is disrupted in a female patient with bilateral congenital retinal folds, microcephaly and mild mental retardation
| Autor: | Merel A.W. Oortveld, Ellen A.W. Blokland, Frans P.M. Cremers, Erik Huys, Jyoti Agrawal, C. Erik van Nouhuys, Dominique Smeets, Eric F.P.M. Schoenmakers, Dorien Lugtenberg, Annette Schenck, Gerard Merkx, Jamie M. Kramer, Arijit Mukhopadhyay, Ad Geurts van Kessel, Hans van Bokhoven |
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| Rok vydání: | 2010 |
| Předmět: |
Adult
Microcephaly Pathology medicine.medical_specialty Genetics and epigenetic pathways of disease [NCMLS 6] Biology Retina Genomic disorders and inherited multi-system disorders [IGMD 3] Species Specificity Intellectual Disability Genetics medicine Animals Drosophila Proteins Humans Genetics(clinical) Abnormalities Multiple In Situ Hybridization Fluorescence Genetics (clinical) DNA Primers Original Investigation Chromosomal inversion Base Sequence medicine.diagnostic_test Genetic heterogeneity Breakpoint Cyclin-Dependent Kinase 8 medicine.disease Cyclin-Dependent Kinases Karyotyping Chromosome Inversion Eye development Chromosomes Human Pair 6 Drosophila Female Falciform retinal fold Haploinsufficiency Functional Neurogenomics [DCN 2] Fluorescence in situ hybridization |
| Zdroj: | Human Genetics Human Genetics, 128, 281-91 Human Genetics, 128, 3, pp. 281-91 |
| ISSN: | 1432-1203 0340-6717 |
| Popis: | Contains fulltext : 88320.pdf (Publisher’s version ) (Closed access) Microcephaly, mental retardation and congenital retinal folds along with other systemic features have previously been reported as a separate clinical entity. The sporadic nature of the syndrome and lack of clear inheritance patterns pointed to a genetic heterogeneity. Here, we report a genetic analysis of a female patient with microcephaly, congenital bilateral falciform retinal folds, nystagmus, and mental retardation. Karyotyping revealed a de novo pericentric inversion in chromosome 6 with breakpoints in 6p12.1 and 6q21. Fluorescence in situ hybridization analysis narrowed down the region around the breakpoints, and the breakpoint at 6q21 was found to disrupt the CDK19 gene. CDK19 was found to be expressed in a diverse range of tissues including fetal eye and fetal brain. Quantitative PCR of the CDK19 transcript from Epstein-Barr virus-transformed lymphoblastoid cell lines of the patient revealed ~50% reduction in the transcript (p = 0.02), suggesting haploinsufficiency of the gene. cdk8, the closest orthologue of human CDK19 in Drosophila has been shown to play a major role in eye development. Conditional knock-down of Drosophila cdk8 in multiple dendrite (md) neurons resulted in 35% reduced dendritic branching and altered morphology of the dendritic arbour, which appeared to be due in part to a loss of small higher order branches. In addition, Cdk8 mutant md neurons showed diminished dendritic fields revealing an important role of the CDK19 orthologue in the developing nervous system of Drosophila. This is the first time the CDK19 gene, a component of the mediator co-activator complex, has been linked to a human disease. 01 september 2010 |
| Databáze: | OpenAIRE |
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