PURPOSE
MAPT, LRRK2, GRN, and C9orf72 are known as responsible genes for several neurological disorders, including progressive supranuclear palsy (PSP), Parkinson's disease (PD), and frontotemporal dementia (FTD). We conducted genetic analysis of a family in which there were several patients with PSP, PD, and FTD over two generations in order to identify the causative gene.
METHODS
We performed high-density SNP typing on 3 affected and 2 unaffected persons, followed by exome sequencing on 3 affected persons. Linkage analysis and Homozygosity Haplotyping based on the results of the high-density SNP analysis exhibited candidate region. Exome sequencing was performed, and the variants were obtained using BWA, Samtools, Picard, and GATK. We reduced the candidates by referring to the public variant databases, and confirmed the remained mutations by Sanger sequencing. In addition, we screened for the mutations on other patients.
RESULTS
Relatively long segments of high LOD score exist on chromosome 6, 9, 14, 17, and 20. Homozygosity Haplotyping indicated common haplotype regions only to the patients in chromosome 13 and 17. From the result of exome sequencing, 2 novel variants were remained finally, and one of the variants was located in microtubule-associated protein tau (MAPT) on chromosome 17. The same variant was observed in the 2 PD patients of another family, and the haplotype around the variant was coincident with that of the index family.
CONCLUSION
The novel MAPT variant we identified is considered to cause neurodegenerative diseases. The variant is located in the region in which several mutations were reported previously, but it is much characteristic that the variant is non-frameshift insertion adding an amino acid. In the further investigation, we hope to reveal the pathogenic mechanism by evaluating biochemical changes associated with the mutation.