Article

The CHRNE 1293insG founder mutation is a frequent cause of congenital myasthenia in North Africa.

AP-HP, UF Cardiogénétique et Myogénétique, Paris, France.
Neurology (impact factor: 8.31). 01/2009; 71(24):1967-72. DOI:10.1212/01.wnl.0000336921.51639.0b pp.1967-72
Source: PubMed

ABSTRACT Mutations in various genes of the neuromuscular junction cause congenital myasthenic syndrome (CMS). A single truncating mutation (epsilon1293insG) in the acetylcholine receptor epsilon subunit gene (CHRNE) was most often identified in CMS families originating from North Africa and was possibly a founder mutation.
Twenty-three families were studied with an early onset form of CMS and originating from Tunisia, Algeria, Morocco, and Libya. Screening for the mutation epsilon1293insG was performed by direct sequencing. Haplotype analysis was done with 9 (CA)n repeat microsatellite markers and 6 SNPs flanking epsilon1293insG on chromosome 17p13-p12. Dating was calculated using the ESTIAGE method for rare genetic diseases.
The epsilon1293insG mutation was identified in 14 families (about 60% of the initial 23). The expression of the CMS in affected members of these families was relatively homogeneous, without fetal involvement or being life-threatening, with moderate hypotonia and oculobulbar involvement, mild and stable disease course, and good response to cholinesterase inhibitors. Haplotype analysis revealed a common conserved haplotype encompassing a distance of 63 kb. The estimated age of the founder event was at least 700 years.
These results strongly support the hypothesis that epsilon1293insG derives from an ancient single founder event in the North African population. Identification of founder mutations in isolated or inbred populations may have important implications in the context of molecular diagnosis and genetic counseling of patients and families by detection of heterozygous carriers.

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    Article: AChR deficiency due to epsilon-subunit mutations: two common mutations in the Netherlands.
    Catharina G Faber, Peter C Molenaar, Johannes S H Vles, Domenic M Bonifati, Jan J G M Verschuuren, Pieter A van Doorn, Jan B M Kuks, John H J Wokke, David Beeson, Marc De Baets
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    ABSTRACT: Congenital myasthenic syndromes are a clinically and genetically heterogeneous group of hereditary disorders affecting neuromuscular transmission. We have identified mutations within the acetylcholine receptor (AChR) epsilon-subunit gene underlying congenital myasthenic syndromes in nine patients (seven kinships) of Dutch origin. Previously reported mutations epsilon1369delG and epsilonR311Q were found to be common; epsilon1369delG was present on at least one allele in seven of the nine patients, and epsilonR311Q in six. Phenotypes ranged from relatively mild ptosis and external ophthalmoplegia to generalized myasthenia. The common occurrence of epsilonR311Q and epsilon1369delG suggests a possible founder for each of these mutations originating in North Western Europe, possibly in Holland. Knowledge of the ethnic or geographic origin within Europe of AChR deficiency patients can help in targeting genetic screening and it may be possible to provide a rapid genetic diagnosis for patients of Dutch origin by screening first for epsilonR311Q and epsilon1369delG.
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  • Article: Founder mutations in Tunisia: implications for diagnosis in North Africa and Middle East.
    Lilia Romdhane, Rym Kefi, Hela Azaiez, Nizar Ben Halim, Koussay Dellagi, Sonia Abdelhak
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Keywords

14 families
 
acetylcholine receptor epsilon subunit gene
 
ancient single founder event
 
CA)n repeat microsatellite markers
 
CMS families originating
 
common conserved haplotype encompassing
 
ESTIAGE method
 
estimated age
 
fetal involvement
 
founder event
 
genetic counseling
 
good response
 
heterozygous carriers
 
initial 23
 
North African population
 
oculobulbar involvement
 
onset form
 
rare genetic diseases
 
single truncating mutation
 
stable disease course