Intragenic CAMTA1 rearrangements cause non-progressive congenital ataxia with or without intellectual disability
| Autor: | Louise Gallagher, Philippe Jonveaux, Virginie Roze, Lydie Burglen, Laurence Duplomb, Perrine Charles, Marlène Bonnet, Delphine Héron, Mylène Béri-Dexheimer, Eloi Magnin, Anne-Laure Mosca-Boidron, Christel Depienne, Nathalie Marle, Cyril Mignot, Boris Keren, Céline Bonnet, Bernard Aral, Alexis Brice, Jeanne Amiel, Virginie Carmignac, Estelle Lopez, Mathieu Anheim, Corinne Mach, Ferechté Razavi, Christel Thauvin-Robinet, Cecilia Altuzarra, Delphine Minot, Jacqueline Vigneron, Laurence Faivre, Emmanuel Haffen, Patrick Callier, Diane Doummar, Sophie Morle, Julien Thevenon |
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| Rok vydání: | 2012 |
| Předmět: |
Adult
medicine.medical_specialty Ataxia Adolescent DNA Copy Number Variations Sequence analysis Biology Bioinformatics Frameshift mutation Molecular genetics Intellectual Disability Genetics medicine Humans Copy-number variation Genetics (clinical) Gene Rearrangement Genetic heterogeneity Point mutation Calcium-Binding Proteins Infant Gene rearrangement Sequence Analysis DNA Middle Aged Pedigree Child Preschool Trans-Activators Female medicine.symptom |
| Zdroj: | Journal of medical genetics. 49(6) |
| ISSN: | 1468-6244 |
| Popis: | Background Non-progressive congenital ataxias (NPCA) with or without intellectual disability (ID) are clinically and genetically heterogeneous conditions. As a consequence, the identification of the genes responsible for these phenotypes remained limited. Objective Identification of a new gene responsible for NPCA and ID. Methods Following the discovery of three familial or sporadic cases with an intragenic calmodulin-binding transcription activator 1 ( CAMTA1 ) rearrangement identified by an array-CGH and recruited from a national collaboration, the authors defined the clinical and molecular characteristics of such rearrangements, and searched for patients with point mutations by direct sequencing. Results Intragenic copy number variations of CAMTA1 were all located in the CG-1 domain of the gene. It segregated with autosomal dominant ID with non-progressive congenital cerebellar ataxia (NPCA) in two unrelated families, and was de novo deletion located in the same domain in a child presenting with NPCA. In the patients with ID, the deletion led to a frameshift, producing a truncated protein, while this was not the case for the patient with isolated childhood ataxia. Brain MRI of the patients revealed a pattern of progressive atrophy of cerebellum medium lobes and superior vermis, parietal lobes and hippocampi. DNA sequencing of the CG-1 domain in 197 patients with sporadic or familial non-syndromic intellectual deficiency, extended to full DNA sequencing in 50 patients with ID and 47 additional patients with childhood ataxia, identified no pathogenic mutation. Conclusion The authors have evidence that loss-of-function of CAMTA1 , a brain-specific calcium responsive transcription factor, is responsible for NPCA with or without ID. Accession numbers CAMTA1 reference sequence used was ENST00000303635. Protein sequence was ENSP00000306522. |
| Databáze: | OpenAIRE |
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