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


CONCLUSIONS
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.
Centre de Génétique et Centre de Référence, Anomalies du Développement et Syndromes Malformatifs, Hôpital d'Enfants, CHU Dijon, Dijon, France.
Julien
J
Thevenon
Estelle
E
Lopez
Boris
B
Keren
Delphine
D
Heron
Cyril
C
Mignot
Cecilia
C
Altuzarra
Mylène
M
Béri-Dexheimer
Céline
C
Bonnet
Eloi
E
Magnin
Lydie
L
Burglen
Delphine
D
Minot
Jacqueline
J
Vigneron
Sophie
S
Morle
Mathieu
M
Anheim
Perrine
P
Charles
Alexis
A
Brice
Louise
L
Gallagher
Jeanne
J
Amiel
Emmanuel
E
Haffen
Corinne
C
Mach
Christel
C
Depienne
Diane
D
Doummar
Marlène
M
Bonnet
Laurence
L
Duplomb
Virginie
V
Carmignac
Patrick
P
Callier
Nathalie
N
Marle
Anne-Laure
AL
Mosca-Boidron
Virginie
V
Roze
Bernard
B
Aral
Ferechte
F
Razavi
Philippe
P
Jonveaux
Laurence
L
Faivre
Christel
C
Thauvin-Robinet
D000293:Adolescent; D000328:Adult; D001259:Ataxia / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics*; D008875:Middle Aged; D010375:Pedigree; D017422:Sequence Analysis, DNA; D015534:Trans-Activators / Q000235:genetics*
C487554:CAMTA1 protein, human; D002135:Calcium-Binding Proteins; D015534:Trans-Activators