OBJECTIVE: We sought to identify a causative mutation in a previously reported kindred with parental consanguinity and 5 of 10 siblings with adult-onset autoimmune myasthenia gravis. METHODS: We performed genome-wide homozygosity mapping, and sequenced all known genes in the one region of extended homozygosity. Quantitative and allele-specific reverse transcriptase PCR (RT-PCR) were performed on a candidate gene to determine the RNA expression level in affected siblings and controls and the relative abundance of the wild-type and mutant alleles in a heterozygote. RESULTS: A region of shared homozygosity at chromosome 13q13.3-13q14.11 was found in 4 affected siblings and 1 unaffected sibling. A homozygous single nucleotide variant was found in the 3'-untranslated region of the ecto-NADH oxidase 1 gene (ENOX1). No other variants likely to be pathogenic were found in genes in this region or elsewhere. The ENOX1 sequence variant was not found in 764 controls. Quantitative RT-PCR showed that expression of ENOX1 decreased to about 20% of normal levels in lymphoblastoid cells from individuals homozygous for the variant and to about 50% in 2 unaffected heterozygotes. Allele-specific RT-PCR showed a 55%-60% reduction in the level of the variant transcript in heterozygous cells due to reduced mRNA stability. CONCLUSION: These results indicate that this sequence variant in ENOX1 may contribute to the familial autoimmune myasthenia in these patients.
OBJECTIVE: We sought to identify a causative mutation in a previously reported kindred with parental consanguinity and 5 of 10 siblings with adult-onset autoimmune myasthenia gravis. METHODS: We performed genome-wide homozygosity mapping, and sequenced all known genes in the one region of extended homozygosity. Quantitative and allele-specific reverse transcriptase PCR (RT-PCR) were performed on a candidate gene to determine the RNA expression level in affected siblings and controls and the relative abundance of the wild-type and mutant alleles in a heterozygote. RESULTS: A region of shared homozygosity at chromosome 13q13.3-13q14.11 was found in 4 affected siblings and 1 unaffected sibling. A homozygous single nucleotide variant was found in the 3'-untranslated region of the ecto-NADH oxidase 1 gene (ENOX1). No other variants likely to be pathogenic were found in genes in this region or elsewhere. The ENOX1 sequence variant was not found in 764 controls. Quantitative RT-PCR showed that expression of ENOX1 decreased to about 20% of normal levels in lymphoblastoid cells from individuals homozygous for the variant and to about 50% in 2 unaffected heterozygotes. Allele-specific RT-PCR showed a 55%-60% reduction in the level of the variant transcript in heterozygous cells due to reduced mRNA stability. CONCLUSION: These results indicate that this sequence variant in ENOX1 may contribute to the familial autoimmune myasthenia in these patients.
Authors: R Bortell; J Moss; R C McKenna; M R Rigby; D Niedzwiecki; L A Stevens; W A Patton; J P Mordes; D L Greiner; A A Rossini Journal: J Immunol Date: 2001-08-15 Impact factor: 5.422
Authors: Guida Landouré; Peng-Peng Zhu; Charles M Lourenço; Janel O Johnson; Camilo Toro; Katherine V Bricceno; Carlo Rinaldi; Katherine G Meilleur; Modibo Sangaré; Oumarou Diallo; Tyler M Pierson; Hiroyuki Ishiura; Shoji Tsuji; Nichole Hein; John K Fink; Marion Stoll; Garth Nicholson; Michael A Gonzalez; Fiorella Speziani; Alexandra Dürr; Giovanni Stevanin; Leslie G Biesecker; John Accardi; Dennis M D Landis; William A Gahl; Bryan J Traynor; Wilson Marques; Stephan Züchner; Craig Blackstone; Kenneth H Fischbeck; Barrington G Burnett Journal: Hum Mutat Date: 2013-08-12 Impact factor: 4.878
Authors: Muthusamy Thiruppathi; Julie Rowin; Qin Li Jiang; Jian Rong Sheng; Bellur S Prabhakar; Matthew N Meriggioli Journal: Ann N Y Acad Sci Date: 2012-12 Impact factor: 5.691