PMC8334358_01
Brain magnetic resonance imaging (MRI) slice-corresponding comparison of the proband for 3 years. Arrows point at progressive atrophy of temporal lobe and hippocampus. A1-A3, B1-B3, and C1-C3 were scanned in August 2018 (2 years after dementia symptom onset in this proband); A4-A6, B4-B6, and C4-C6 were scanned in July 2019; and A7-A9, B7-B9, and C7-C9 were scanned in July 2020. (A) Axial T1WI: each column revealed progressive atrophy of the left-dominant bilateral temporal lobe and hippocampus. (B) Left-side sagittal T1WI: focused on the left part of the hippocampus. (C) Right-side sagittal T1WI: focused on the right part of the hippocampus.
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F2
Her brain MRI revealed progressive atrophy of the left-dominant bilateral temporal lobe and hippocampus (Figure 2).
PMC8334358_02
(A) Pedigree of early-onset Alzheimer's disease with the PSEN2 Phe369Ser mutation. The proband is marked with an arrow; circles and squares represent females and males, respectively; filled symbols, affected family members; half-filled symbols, mutation carriers (currently with no clinical symptoms of EOAD). Blood samples were available from the proband (II: 1), her sister (II: 3), brothers (II: 5, II: 7), and her daughters (III: 1, III: 2). (B) DNA sequencing chromatography indicated a heterozygous PSEN2 c.1106T>C mutation (nomenclature according to NCBI. Reference Sequence: NM_000447.2) in the proband and her two daughters. (C) Evolutionary conservation analysis of phenylalanine (Phe or F) at position 369 among different species.
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F1
The proband had a positive family history (Figure 1A). The proband's sister (Figure 1A II: 3, 53 years old) and two brothers (Figure 1A II: 5, 50 years old; II: 7, 47 years old) exhibited normal cognitive status. The proband's two daughters (Figure 1AIII: 1, 29 years old; III: 2, 26 years old) were PSEN2 Phe369Ser mutation carriers. Target region capture sequencing uncovered a novel heterozygous missense variant (NM_000447.2: c.1106T>C) in the proband located at exon 11 of PSEN2, which caused a substitution from phenylalanine (Phe or F) to serine (Ser) at codon 369 (Phe369Ser) (Figure 1B). The evolutionarily conservative prediction revealed that missense mutation p.Phe368Ser led to a highly conserved amino acid change (Figure 1C). 3D protein structures of wild-type and mutant PSEN2 superimposition displayed the substitution from phenylalanine to serine at position 369 (Figure 3).
3D structure prediction of the PSEN2 p.Phe369Ser mutation. Wild-type PSEN2 N-terminus: light blue; mutant PSEN2 N-terminus: light pink; wild-type PSEN2 C-terminus: marine blue; mutant PSEN2 C-terminus: magenta. Catalytic aspartate on transmembrane domain 7 is colored orange. Wild-type and mutant residues in position 369 of PSEN2 are highlighted in yellow and green, respectively. (A) Zoomed-in view of the mutant PSEN2 C-terminus. (B) Zoomed-in view of the wild-type PSEN2 C-terminus. (C) Zoomed-in view of the superimposed wild-type and mutant PSEN2 C-terminus, which displayed substitution of phenylalanine by serine at codon 369 (Phe369Ser).
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F3
The evolutionarily conservative prediction revealed that missense mutation p.Phe368Ser led to a highly conserved amino acid change (Figure 1C). 3D protein structures of wild-type and mutant PSEN2 superimposition displayed the substitution from phenylalanine to serine at position 369 (Figure 3).