Seong An

PSEN1 p.Thr116Ile Variant in Two Korean Families with Young Onset Alzheimer’s Disease

An in depth study of PSEN1 mutation p.Thr116Ile (c.335C>T) is presented from two Korean families with autosomal dominant inheritance. Clinical manifestation of our patients included memory loss, attention deficits, visuospatial dysfunction, agnosia, aphasia, apraxia, and personality changes, which occurred in their 30s. PSEN1 Thr116Ile was initially discovered in an Italian patient and two French families with early onset Alzheimer’s disease (EOAD) with similar age of onset. To verify the possible pathogenic mechanisms of mutation, in silico predictions and 3D modeling were performed. Structure predictions revealed significant aberrations in first hydrophilic loop (HL-I loop). The hydrophobic isoleucine could alter the loop orientation through increased hydrophobic contacts with the surrounding amino acids. Mutation could destroy a possible hydrogen bond between tyrosine 115 and threonine 116, which may affect the loop conformation. HL-I was confirmed as a conservative region of PSEN1, which may be critical in PSEN1 functions. An additional pathogenic mutation, PSEN1 Thr116Asn, was also found for the same residue, where the patient presented young onset AD (YOND). Other mutations in HL-I loop, such as Tyr115His and Glu120Asp, were described in patients with YOND, supporting the critical role of HL-I loop in PSEN1 activity.

Genetic analysis of PGRN and MAPT genes in Koreans with diverse neurodegenerative disorders

Background: A number of mutations in the gene encoding microtubule associated protein tau, MAPT, are located in exon 10 or in the flanking intronic regions. These mutations have been shown to affect alternative splicing of exon 10, resulting in increased production of tau protein containing four repeats of the microtubule binding domains. Here we describe a novel variation upstream of exon 10 in a patient clinically diagnosed with frontotemporal dementia with a positive family history of dementia. Methods:MAPT mutation analysis was performed by direct sequencing of exons 1, 9-13 and the flanking intronic regions. Neuropathological analysis was performed using routine histopathological methods and immunohistochemical analysis was performed with antibodies recognizing different phospho-epitopes in the tau protein on formalin-fixed paraffin embedded sections. Results: Sequencing of the MAPT gene revealed a silent mutation in the coding region (P207P), previously reported to be non-pathogenic. In addition we identified a previously unknown variation in intron 9 (IVS9-11G>C), located in the polypyrimidine tract upstream of exon 10. The neuropathological assessment demonstrated neuronal loss which was most evident in frontal and temporal cortices, hippocampus and substantia nigra. Abundant phospho-tau immunopositive neuronal cytoplasmic inclusions and oligodendroglial coiled bodies were found. Conclusions: The novel variation in intron 9 of MAPT is located in the polypyrimidine tract upstream of exon 10, which previously have been suggested to affect the splicing of exon 10. Further studies are needed to determine whether the IVS9-11G>C variation is pathogenic, but the current literature suggests that this variation might affect splicing of MAPT resulting in an increase in four-repeat tau isoforms.

Genetic analysis of Korean early Alzheimer's and dementia patients

Eva Bagyinszky, Min A. Yee, Yooseok Kwon, Youngcheol Youn, Seong An, SangYun Kim, Gachon University BioNano Department, Seongnam-si, South Korea; Gachon University, Seongnam-si, South Korea; Seoul National University College of Medicine & Seoul National University Bundang Hospital, Seongnam-si, South Korea; 4 Chungang University, Seoul, South Korea; 5 Gachon University, Sungnam-si, South Korea; Seoul National University, Seongnam-si, Kyungki-do, South Korea.