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

Abstract

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.

Keywords: PSEN1 Thr116Ile mutation; familial; mutation; presenilin-1; young onset Alzheimer’s dementia.

Figure 1

(a) Sequencing data of proband patient from Family 1 with PSEN1 T116I; (b) sequencing data of proband patient from Family 1 with PSEN1 T116I; and (c) SSCP data on PSEN1 T116I in Family 1. Number 2** is the proband patient and Number 4* is her affected sister. Numbers 1 and 3 are the asymptomatic and unaffected sisters. The ”C” means the control band, a PCR product of an individual, who was verified as wild type for PSEN1 exon 5. Star means that these individuals are affected with mutation.

Figure 1

(a) Sequencing data of proband patient from Family 1 with PSEN1 T116I; (b) sequencing data of proband patient from Family 1 with PSEN1 T116I; and (c) SSCP data on PSEN1 T116I in Family 1. Number 2** is the proband patient and Number 4* is her affected sister. Numbers 1 and 3 are the asymptomatic and unaffected sisters. The ”C” means the control band, a PCR product of an individual, who was verified as wild type for PSEN1 exon 5. Star means that these individuals are affected with mutation.

Figure 2

ExPASY prediction on PSEN T116I: (a) Kyte and Dootile hydrophobicity scores; (b) bulkiness scores; and (c) polarity scores.

Figure 3

3D modeling on PSEN1 Thr116Ile mutation, compared to the normal PSEN1. Threonine is labeled with blue while Isoleucine is labeled with yellow. Mutation could disturb significantly the HL-I loop structure.

Figure 4

3D model on PSEN1 Thr116Ile mutation, in terms intramolecular interactions. (a) Thr116 (blue) could form hydrogen bond with Tyr115 (orange) and may form hydrophobic interactions with Pro117 (green). (b) In the case of Ile116 (yellow), both contacts could be lost, and an additional hydrophobic interaction would be formed with Ile114 (purple).

Figure 5

Mutations, located in the HL-I of PSEN1 protein.

Figure 6

(a) Family tree of patient with PSEN1 T116I mutation (Family 1); and (b) family tree of patient with PSEN1 T116I mutation (Family 2). This figure was adapted and reprinted with the permission from Dove Medical Press (Clinical Interventions in Aging) [11]. White circles mean asymptomatic patients, which were not diagnosed with disease. Family members which were crossed out, already died. Arrows show the proband patient. Question mark at the grandparents means that their disease status is unclear.

Figure 7

(a) MRI data of proband patient of Family 1. Atrophy could be seen in the right temporal and parietal regions. A vascular abnormality also appeared in the left frontal area. (b) MRI data of proband patient of Family 2. (c) PET data from Family 2.