Intragenic<i>CAMTA1</i>rearrangements cause non-progressive congenital ataxia with or without intellectual disability

Thévenon, Julien; Lopez, Estelle; Keren, Boris; Héron, Delphine; Mignot, Cyril; Altuzarra, Cécilia; Béri-Dexheimer, Mylène; Bonnet, Céline; Magnin, Éloi; Bürglen, 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; Rozé, Virginie; Aral, Bernard; Razavi, F.; Jonveaux, Philippe; Faivre, Laurence; Thauvin‐Robinet, Christel

doi:10.1136/jmedgenet-2012-100856

Cited by 45 publications

(65 citation statements)

References 35 publications

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“…In this regard, multiple SNPs that correlate to cognitive abnormalities have been identified in the CAMTA1 gene (8). The importance of CAMTA1 for normal neurological function was highlighted further by the identification of human subjects with heterozygous chromosomal rearrangements in the CAMTA1 locus who present with congenital cerebellar ataxia, in accord with our findings in mice (9). It should be emphasized, however, that these human phenotypes result from heterozygous CAMTA1 mutations, whereas the abnormalities observed in mice result from homozygous gene deletion.…”

Section: Discussionsupporting

confidence: 81%

“…Previous studies reported strong expression of CAMTA1 in the cerebellum, as well as in the hippocampi and olfactory bulbs of embryonic and neonatal mice (9). Consistent with these findings, in situ hybridization of adult brain sections with CAMTA1-specific probes showed that CAMTA1 transcripts were highly enriched in the cerebellum (Fig.…”

Section: Significancesupporting

confidence: 85%

“…The functions of CAMTA1 have not been analyzed in mice. However, haploinsufficiency of CAMTA1, caused by mutations and genomic rearrangements, has been shown to cause sporadic and familial nonsyndromic intellectual deficiency and childhood ataxia in humans (8,9). The mechanistic basis of these abnormalities has not been defined.…”

mentioning

confidence: 99%

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Ataxia and Purkinje cell degeneration in mice lacking the CAMTA1 transcription factor

Long

Grueter

Song

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Neurodegenerative diseases are debilitating conditions that result from degeneration of the nervous system causing symptoms including ataxia and/or dementia. Calmodulin-binding transcription activator 1 (CAMTA1) is a transcription factor enriched in the brain with the highest levels of expression in the cerebellar granular layer and Purkinje cells, midbrain, pons, and hippocampus. When CAMTA1 is deleted from the nervous system of mutant mice, we observe a clear loss of Purkinje cells and reduced cerebellar size. Thus, we conclude that CAMTA1 plays a predominant role in the maturation and survival of cerebellar neurons rather than in the initial development of these cells. The neurological abnormalities associated with CAMTA1-mutant mice allow mechanistic analysis of these abnormalities and disease modeling.

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Section: Discussionsupporting

confidence: 81%

Section: Significancesupporting

confidence: 85%

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Ataxia and Purkinje cell degeneration in mice lacking the CAMTA1 transcription factor

Long

Grueter

Song

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Since its development, high-resolution array-CGH has shown its ability to detect intragenic copy-number variations (CNVs) and has highlighted the implication of new genes in ID, in particular in autosomal dominant familial ID (Thevenon et al 2012). Differentiating between benign and pathogenic CNVs could be a challenge, as it depends on the size, the genes involved, and the mode of inheritance.…”

Section: Discussionmentioning

confidence: 99%

Homozygous Truncating Intragenic Duplication in TUSC3 Responsible for Rare Autosomal Recessive Nonsyndromic Intellectual Disability with No Clinical or Biochemical Metabolic Markers

Chehadeh

Bonnet²,

Callier

et al. 2014

JIMD Reports

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Intellectual disability (ID), which affects around 2-3% of the general population, is classically divided into syndromic and nonsyndromic forms, with several modes of inheritance. Nonsyndromic autosomal recessive ID (NS-ARID) appears extremely heterogeneous with numerous genes identified to date, including inborn errors of metabolism. The TUSC3 gene encodes a subunit of the endoplasmic reticulum (ER)-bound oligosaccharyltransferase complex, which mediates a key step of N-glycosylation. To date, only five families with NS-ARID and TUSC3 mutations or rearrangements have been reported in the literature. All patients had speech delay, moderate-to-severe ID, and moderate facial dysmorphism. Microcephaly was noted in one third of patients, as was short stature. No patients had congenital malformation except one patient with unilateral cryptorchidism. Glycosylation analyses of patients' fibroblasts showed normal N-glycan synthesis and transfer. We present a review of the 19 patients previously described in the literature and report on a sixth consanguineous family including two affected sibs, with intellectual disability, unspecific dysmorphic features, and no additional malformations identified by high-resolution array-CGH. A homozygous truncating intragenic duplication of the TUSC3 gene leading to an aberrant transcript was detected in two siblings. This observation, which is the first reported case of TUSC3 homozygous duplication, confirms the implication of TUSC3 in NS-ARID and the power of the high-resolution array-CGH in identifying intragenic rearrangements of genes implicated in nonsyndromic ID and rare diseases.

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“…95 Similar genotype-phenotype correlations are beginning to be explored and have been proposed for genes including NRXN1, 96,97 AUTS2, 98 MEF2C, 99 and CAMTA1. 100 These correlations are mainly based on clinical observations, but model organism data 98 and examination of transcriptional products from CNV carriers 100 provide some additional support.…”

Section: Genotype-phenotype Correlationsmentioning

confidence: 99%

Chromosomal Microarrays: Understanding Genetics of Neurodevelopmental Disorders and Congenital Anomalies

Patel

Rosenfeld

2016

J Pediatr Genet

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IntragenicCAMTA1rearrangements cause non-progressive congenital ataxia with or without intellectual disability

Abstract: 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.

Cited by 45 publications

References 35 publications

Ataxia and Purkinje cell degeneration in mice lacking the CAMTA1 transcription factor

Ataxia and Purkinje cell degeneration in mice lacking the CAMTA1 transcription factor

Homozygous Truncating Intragenic Duplication in TUSC3 Responsible for Rare Autosomal Recessive Nonsyndromic Intellectual Disability with No Clinical or Biochemical Metabolic Markers

Chromosomal Microarrays: Understanding Genetics of Neurodevelopmental Disorders and Congenital Anomalies

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