Intragenic CAMTA1 rearrangements cause non-progressive congenital ataxia with or without intellectual disability

  • J Med Genet. 2012 Jun;49(6):400-8. doi: 10.1136/jmedgenet-2012-100856.
Julien Thevenon  1 ,  Estelle Lopez ,  Boris Keren ,  Delphine Heron ,  Cyril Mignot ,  Cecilia Altuzarra ,  Mylène Béri-Dexheimer ,  Céline Bonnet ,  Eloi Magnin ,  Lydie Burglen ,  Delphine Minot ,  Jacqueline Vigneron ,  Sophie Morle ,  Mathieu Anheim ,  Perrine Charles ,  Alexis Brice ,  Louise Gallagher ,  Jeanne Amiel ,  Emmanuel Haffen ,  Corinne Mach ,  Christel Depienne ,  Diane Doummar ,  Marlène Bonnet ,  Laurence Duplomb ,  Virginie Carmignac ,  Patrick Callier ,  Nathalie Marle ,  Anne-Laure Mosca-Boidron ,  Virginie Roze ,  Bernard Aral ,  Ferechte Razavi ,  Philippe Jonveaux ,  Laurence Faivre ,  Christel Thauvin-Robinet
Affiliations
  • 1. Centre de Génétique et Centre de Référence, Anomalies du Développement et Syndromes Malformatifs, Hôpital d'Enfants, CHU Dijon, Dijon, France.
PMID: 22693284 DOI: 10.1136/jmedgenet-2012-100856
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.