Genetic origin of a large family with a novel PSEN1 mutation (Ile416Thr)

Abstract

Introduction: A small percentage of Alzheimer's disease (AD) cases are caused by genetic mutations with autosomal dominant inheritance. We report a family with a novel variant in PSEN1.

Methods: We performed clinical and genetic evaluation of 93 related individuals from a Colombian admixed population. 31 individuals had whole-genome sequencing.

Results: Genetic analysis revealed a missense variant in PSEN1 (NM_000021.3: c.1247T>C p.Ile416Thr), which originated on an African haplotype and segregated with AD logarithm of the odds score of 6. Their clinical phenotype is similar to sporadic AD except for earlier age at onset: the mean age at onset for mild cognitive impairment was 47.6 years (standard deviation 5.83) and for dementia 51.6 years (standard deviation 5.03).

Discussion: Ile416Thr is a novel pathogenic variant that causes AD in the sixth decade of life. The history of the region that included slave importation and admixtures within a confined geographic locale represents a "mini-population bottleneck" and subsequent emergence of a rare dominant mutation.

Trial registration: ClinicalTrials.gov NCT01998841.

Keywords: Admixture in Latin America; Autosomal dominant Alzheimer's disease; Founder effect; Genetic Bottleneck; Genetic drift; Phenotype genotype correlation; Presenilin 1.

Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare no conflicts of interest on the research, authorship, and/or publication of this study. Francisco Lopera, M.D. and Margarita Giraldo, M.D. are investigators at API-Colombia clinical trial for genetic Alzheimer’s Disease (NCT01998841).

Copyright © 2018 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.. PEDRIGREE OF THE FAMILY.

The diagram represents the extended family, square for male and circle for female. Individuals with MCI and dementia have been classified as symptomatic and are represented as filled icons, empty icons represent asymptomatic individuals. Individuals from whom we have information but died before the study were represented as deceased (crossed out). All 93 participants in the study were labeled with age at onset for MCI (if applicable), age at onset for Dementia (if applicable), and age at the clinical evaluation. If the age at onset was unknow the data was labeled as Not Available (NA). The symptomatic individuals from the V generation met the MCI criteria, but none of them met dementia criteria, therefore AAO for dementia was not registered. MCI: Mild cognitive impairment, AAE: age at examination, NA: data not available * Individual with whole genome sequencing data, + Individual used for zygosity mapping.

Figure 2.

A: schematic representation of Preselenin 1 in the cell membrane. Residues that have variants known to cause Alzheimer’s disease are represented with a red border [3]. Residue 416 in TM VIII is colored in red. TM: Transmembrane B: Color chromatogram depicting the missense variant in the PSEN1 gene. C: Alignment of PSEN1 ortologs (uniprot.org). Residue 416 is highlighted in yellow. * Residues that are conserved among the 5 species. • Residues that are conserved at least in 4 species. : Residues that are conserved at least in 3 species.

Figure3.. AGE DEPENDANT COGNITIVE DECLINE IN CARRIERS AND NON-CARRIERS.

FAST: Functional Assesment Staging Tool. FAST score was converted into a linear scale, where 6a corresponds to 6, 6b to 7 and so on until 16. Lineal and curvilinear models were used to represent, in non-carriers and carriers, respectively, the relation between the FAST (A) and the Minimental State Examination (MMSE) score (B) and the age at assessment (in years) centered at 40 years (mean of all data). Individuals with overlapping ages and scores were represented as a single point. Model for non-carriers FAST: Expected mean FAST= 1.43+0.016agecentered. CI95% Intercept (1.314 – 1.546). CI95% agecentered coefficient (0.008-0.023). Model for carriers FAST: Expected mean FAST= 1.69+0.16agecenterd+0.0064agecenterd2. CI95% Intercept (0.651 – 2.723). CI95% agecentered coefficient (0.099-0.223). CI95% agecentered2 coefficient (0.002-0.010).Model for non-carriers MMSE: Expected mean MMSE= 27.3 to 0.099agecenterd. CI95% Intercept (26.68 to 27.90). CI95% agecentered coefficient (−0.139 to −0.058). Model for carriers MMSE: Expected mean MMSE= 27.2-0.46agecenterd-0.02agecentered2. CI95% Intercept (24,778 to 29.580). CI95% agecentered coefficient (−0.603 to −0.307). CI95% agecentered2 coefficient (−0.028 to −0.006).

Figure 4. SPATIAL PATTERNS OF [11C] PIB AND [18F] FTP BINDING IN ILE416THR PSEN1 MUTATION CARRIERS.

PET maps are shown for two cognitively unimpaired carriers (MMSE>27) and one age-matched non-carrier family member. Sagittal PiB DVR maps are shown on the left, and sagittal FTP SUVR maps are presented on the right. Images are displayed in standardized atlas space, along with whole-brain surface renderings, with a left hemisphere view. Row A) A cognitively unimpaired carrier with high cortical amyloid (DVR=1.39) and with FTP binding in entorhinal cortex (SUVR=1.35). B) A cognitively unimpaired carrier with higher cortical amyloid (DVR=1.41), and FTP binding in entorhinal cortex (SUVR=1.12). C) An age-matched unimpaired non-carrier with low amyloid by PiB PET (DVR=1.10) and low FTP binding in entorhinal cortex (SUVR=1.11). PET: positron emission tomography, MMSE: Minimental State Exammination, PiB: Pittsburgh Compound B , DVR: Distribution volume ratio, FTP: Flortaucipir, SUVR: Standardized uptake value ratio.

Figure 5. IDENTIFICATION OF AN ILE416THR-ASSOCIATED HAPLOTYPE IN THE COPACABANA FAMILY.

Haplotype analysis of phased genotypes from 22 Ile416Thr variant carriers and 9 non-carriers (n = 31) identified seven haplotypes composed of 16 single nucleotide polymorphism (SNPs) spanning 86,664 base pairs on chromosome 14. This haplotype spanned exons 4 – 12 of PSEN1, including the Ile416Thr variant (last amino acid of exon 11, and exons 1 - 10 of PAPLN. The combination of alleles for all 16 SNPs in each of the seven identified haplotypes are provided in the table in the top panel. A single copy of one haplotype was found exclusively in all variant carriers and was absent from all non-variant carriers (I416T+, last row of top panel table). Recombination rates are represented in centimorgans per megabase, and were obtained from the hg19 genetic map provided as part of the Eagle v2.4 package and. The red arrowheads point to the site of the Ile416Thr mutation. Freq: frequency.