Mapping of the second Friedreich's ataxia (FRDA2) locus to chromosome 9p23-p11: evidence for further locus heterogeneity

Friedreich's ataxia (FRDA), the most-common form of autosomal recessive ataxia, is inherited in most cases by a large expansion of a GAA triplet repeat in the first intron of the frataxin (X25) gene. Genetic heterogeneity in FRDA has been previously reported in typical FRDA families that do not link to the FRDA locus on chromosome 9q13. We report localization of a second FRDA locus (FRDA2) to chromosome 9p23-9p11, and we provide evidence for further genetic heterogeneity of the disease, in a family with the classic FRDA phenotype

Mapping of the familial infantile myasthenia (congenital myasthenic syndrome type Ia) gene to chromosome 17p with evidence of genetic homogeneity

Familial infantile myasthenia is an autosomal recessive disorder, recently classified as congenital myasthenic syndrome type la, Onset of symptoms is at birth to early childhood with significant myasthenic weakness and possible respiratory distress, followed later in life by symptoms of mild to moderate myasthenia, Thirty-six patients of 12 families, seven of them consanguineous, were used to map the familial infantile myasthenia gene. A combination of linkage search through the genome, DNA pooling and homozygosity mapping were employed resulting in the localisation of this disease locus to the telomeric region of chromosome 17p. A maximum led score of 9.28 at theta = 0.034 was obtained between the disease locus and marker locus D17S1537, Haplotype analysis showed all families to be consistent with linkage to this region thus providing evidence for genetic homogeneity of familial infantile myasthenia. Multipoint linkage analysis mapped the disease gene in the similar to 4.0 cM interval between marker loci D17S1537 and D17S1298 with a maximum multipoint lod score of 12.07. Haplotype analysis and homozygosity by descent in affected individuals of the consanguineous families revealed results in agreement with the confinement of the familial infantile myasthenia region within the interval between marker loci D17S1537 and D17S1298

Chromosome 17p-linked myasthenias stem from defects in the acetylcholine receptor epsilon-subunit gene

Objective: To identify and to characterize functionally the mutational basis of congenital myasthenic syndromes (CMS) linked to chromosome 17p. Background: A total of 37 patients belonging to 13 CMS families, 9 of them consanguineous, were investigated. All patients were linked previously to the telomeric region of chromosome 17p. Two candidate genes in this region encode synaptobrevin 2, a presynaptic protein, and the epsilon-subunit of the acetylcholine receptor (AChR). Direct sequencing of the synaptobrevin 2 gene revealed no mutations. The authors thus searched for mutations in the epsilon-subunit gene of AChR. Methods: Direct sequencing of the AChR epsilon-subunit, restriction analysis, allele-specific PCR, and expression studies in human embryonic kidney cells were performed. Results: The authors identified two previously characterized and five novel epsilon-subunit gene mutations, all homozygous, in the 13 kinships. Two of the novel mutations are truncating (epsilon 723delC and epsilon 760ins8), one is a missense mutation in the signal peptide region (epsilon V-13D), one is a missense mutation in the N-terminal extracellular domain (epsilon T51P), and one is a splice donor site mutation in intron 10 (epsilon IVS10+2T-->G). Unaffected family members have no mutations or are heterozygous. Expression studies indicate that the four novel mutations in the coding region of the gene and the most likely transcript of the splice-site mutation, which skips exon 10, are low-expressor or null mutations. Conclusions: Chromosome 17p-linked congenital myasthenic syndromes are caused by low-expressor/null mutations in the AChR epsilon-subunit gene. Mutations in this gene are a common cause of CMS in eastern Mediterranean countries