Intragenic CAMTA1 rearrangements cause non-progressive congenital ataxia with or without intellectual disability. Issue 6 (12th June 2012)

• Record Type: Journal Article
• Authors: Thevenon, Julien; Lopez, Estelle; Keren, Boris; Heron, Delphine; Mignot, Cyril; Altuzarra, Cecilia; Béri-Dexheimer, Mylène; Bonnet, Céline; Magnin, Eloi; Burglen, Lydie; Minot, Delphine; Vigneron, Jacqueline; Morle, Sophie; Anheim, Mathieu; Charles, Perrine; Brice, Alexis; Gallagher, Louise; Amiel, Jeanne; Haffen, Emmanuel; Mach, Corinne; Depienne, Christel; Doummar, Diane; Bonnet, Marlène; Duplomb, Laurence; Carmignac, Virginie; Callier, Patrick; Marle, Nathalie; Mosca-Boidron, Anne-Laure; Roze, Virginie; Aral, Bernard; Razavi, Ferechte; Jonveaux, Philippe; Faivre, Laurence; Thauvin-Robinet, Christel;
• Is Part Of: Journal of medical genetics. Volume 49:Issue 6(2012)
• Page Start: 400
• Page End: 408
• Publication Date: 2012-06-12
• Subjects: 1p36.31 micro deletion -- intragenic rearrangement -- CAMTA1 gene -- autosomal dominant intellectual disability -- non-progressive congenital ataxia -- genetics -- molecular genetics -- cytogenetics -- neurology -- memory disorders -- clinical genetics -- epilepsy and seizures -- multiple sclerosis -- neurosciences -- genetic screening/counselling -- psychiatry -- mood disorders (including depression) -- developmental; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2012-100856
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : 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.