Non-coding repeat expansions with same repeat motifs in three genes cause benign adult familial myoclonic epilepsy.
Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo and Institute of Medical Genomics, International University of Health and Welfare
Unstable tandem repeat expansions have been shown to be involved in a wide variety of neurological diseases. Given a rapidly increasing number of diseases belonging to this group, it is expected that many more diseases await identification of causative genes. We have recently identified non-coding repeat expansions in benign adult familial myoclonic epilepsy (BAFME), an autosomal dominant disorder characterized by infrequent epilepsy and myoclonic tremor. The clue for identification of non-coding repeat expansion was obtained by an observation of a TTTTA pentanucleotide repeat located in intron 4 of SAMD12, which showed an apparently inconsistent transmission pattern in a family. An intensive search of the whole genome sequence data revealed TTTCA and TTTTA repeat expansions in intron 4 of SAMD12, which were found exclusively in the patients in the 51 families. RNA foci consisting of UUUCA repeats, but not of UUUUA repeats, were observed in neurons of the autopsied brains. Intriguingly, similar TTTCA and TTTTA repeat expansions were further identified in introns of TNRC6A and RAPGEF2, in patients with the clinical diagnosis with BAFME, who did not carry TTTCA repeat expansions in SAMD12. The findings that the same expanded repeat motifs in the three independent genes lead to BAFME phenotypes emphasize the role of TTTCA repeat expansions in BAFME, presumably through RNA-mediated toxicity, which was further supported by the presence of RNA foci without ubiquitinated inclusions. Based on these observations, we propose a new concept of “repeat motif-phenotype correlation”. We are currently applying this strategy to further identify non-coding repeat expansions in neurological diseases.