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Original Investigation |

SYNE1 Mutations in Autosomal Recessive Cerebellar Ataxia

Anne Noreau, MSc1,2; Cynthia V. Bourassa, MSc1,2; Anna Szuto, MSc1,2; Annie Levert, DEC1,2; Sylvia Dobrzeniecka, MSc1,2; Julie Gauthier, PhD1,4; Sylvie Forlani, PhD5; Alexandra Durr, MD, PhD5,6; Mathieu Anheim, MD, PhD5,6,7; Giovanni Stevanin, PhD5,6,8; Alexis Brice, MD, PhD5; Jean-Pierre Bouchard, MD, FRCPD9; Patrick A. Dion, PhD1,2,3; Nicolas Dupré, MD, FRCPC9; Guy A. Rouleau, MD, PhD, FRCPC, OQ1,2
[+] Author Affiliations
1Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal, Quebec, Canada
2Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada
3Department of Pathology and Cellular Biology, Université de Montréal, Montreal, Quebec, Canada
4Research Center, Centre Hopitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada
5Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, Inserm U975, Pitie-Salpetriere Hospital, Paris, France
6Department of Genetics, Assistance Publique Hopitaux de Paris, Pitie-Salpetriere Hospital, Paris, France
7Department of Neurology, Hopital Civil, Strasbourg, France
8Laboratoire de Neurogénétique de l’Ecole Pratique des Hautes Etudes, Pitie-Salpetriere Hospital, Paris, France
9Department of Neurological Sciences and Faculty of Medicine, Laval University, Centre Hopitalier Universitaire de Québec, Quebec City, Quebec, Canada
JAMA Neurol. 2013;70(10):1296-1301. doi:10.1001/jamaneurol.2013.3268.
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Importance  Autosomal recessive cerebellar ataxia type I, also known as recessive ataxia of Beauce, is a slowly progressive ataxia that leads to moderate disability with gait ataxia, dysarthria, dysmetria, mild oculomotor abnormalities, and diffuse cerebellar atrophy on brain imaging. Mutations in the synaptic nuclear envelope protein 1 (SYNE1) gene, located on chromosome 6p25, were first reported in patients who originated from a region known as “Beauce” in the province of Quebec, Canada.

Objective  To better evaluate the prevalence of SYNE1 mutations in individuals with mild pure cerebellar ataxia and cerebellar atrophy, we screened the gene in additional French-Canadian (FC) families and individuals from other populations.

Design, Setting, and Participants  Study participants were referred by their treating physician on the basis of core features of autosomal recessive cerebellar ataxia type I. After excluding individuals with known SYNE1 mutations, our cohort was composed mainly of 19 FCs and 21 individuals from other ethnic backgrounds.

Interventions  Extraction of DNA from blood samples and complete resequencing of the SYNE1 gene.

Main Outcomes and Measures  The involvement of SYNE1 mutations in individuals with ataxia worldwide by resequencing the SYNE1 gene.

Results  Two novel truncating mutations were found among the FC participants, and 2 other novel mutations were found in a patient from France and a patient from Brazil (1 mutation each).

Conclusions and Relevance  This is the second report, to our knowledge, of SYNE1 gene mutations in a population other than FCs. These data suggest that mutations in SYNE1 should be investigated in families with cerebellar ataxia who live outside the FC region.

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Figure 1.
French-Canadian Family A

A, Pedigree of French-Canadian family A. A square indicates male; circle, female; open symbol, unaffected; solid symbol, affected; slash, deceased; N, normal or unaffected (seen by a neurologist and confirmed N); and square around the symbol, proband. B, Amino acid sequences of the mutation are followed by a chromatogram from an unaffected family member (WT) compared with a chromatogram from an affected family member who carries the 2 new mutations (Mutated). C, Affectation status of 7 family members and segregation of the mutations in the family.

Graphic Jump Location
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Figure 2.
French-Canadian Family B

A, Pedigree of French-Canadian family B. The pedigree symbols are explained in Figure 1. B, Amino acid sequences of the mutation are followed by a chromatogram of an unaffected family member (WT) compared with a chromatogram from an affected family member who carries the new mutation (Mutated). C, Affectation status of 10 family members and segregation of the mutations in the family.

Graphic Jump Location
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Figure 3.
Sporadic Case A, an Individual Who Originated From Brazil

A, Amino acid sequences of the mutation are followed by a chromatogram of an unaffected individual (WT) compared with a chromatogram from this affected individual from Brazil who carries the new homozygous mutation (Mutated). B, Clinical status and segregation of the mutation for sporadic case A.

Graphic Jump Location
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Figure 4.
Sporadic Case B, an Individual Who Originated From France

A, Amino acid sequences of the mutation are followed by a chromatogram of an unaffected individual (WT) compared with a chromatogram from this affected individual from France who carries the new mutation (Mutated). New amino-acid translation according to a prediction program (NNSPLICE, version 0.9; www.fruitfly.org/seq_tools/splice.html). This 5-nucleotide deletion will lead to the reaction of a valine followed by an isoleucine (I), a lysine (K), and a stop codon (X). B, Clinical status and segregation of the mutation for sporadic case B.

Graphic Jump Location

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