<i>PSEN1</i> His214Asn Mutation in a Korean Patient with Familial EOAD and the Importance of Histidine–Tryptophan Interactions in TM-4 Stability
A pathogenic mutation in presenilin-1 (<i>PSEN1</i>), His214Asn, was found in a male patient with memory decline at the age of 41 in Korea for the first time. The proband patient was associated with a positive family history from his father, paternal aunt, and paternal grandmother withou...
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MDPI AG
2023-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/1/116 |
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| author | Eva Bagyinszky Minju Kim Young Ho Park Seong Soo A. An SangYun Kim |
| author_facet | Eva Bagyinszky Minju Kim Young Ho Park Seong Soo A. An SangYun Kim |
| author_sort | Eva Bagyinszky |
| collection | DOAJ |
| description | A pathogenic mutation in presenilin-1 (<i>PSEN1</i>), His214Asn, was found in a male patient with memory decline at the age of 41 in Korea for the first time. The proband patient was associated with a positive family history from his father, paternal aunt, and paternal grandmother without genetic testing. He was diagnosed with early onset Alzheimer’s disease (EOAD). <i>PSEN1</i> His214Asn was initially reported in an Italian family, where the patient developed phenotypes similar to the current proband patient. Magnetic resonance imaging (MRI) scans revealed a mild hippocampal atrophy. The amyloid positron emission tomography (amyloid-PET) was positive, along with the positive test results of the increased amyloid ß (Aβ) oligomerization tendency with blood. The <i>PSEN1</i> His214 amino acid position plays a significant role in the gamma–secretase function, especially from three additional reported mutations in this residue: His214Asp, His214Tyr, and His214Arg. The structure prediction model revealed that PSEN1 protein His214 may interact with Trp215 of His-Trp cation-π interaction, and the mutations of His214 would destroy this interaction. The His-Trp cation-π interaction between His214 and Trp215 would play a crucial structural role in stabilizing the 4th transmembrane domain of PSEN1 protein, especially when aromatic residues were often reported in the membrane interface of the lipid–extracellular region of alpha helices or beta sheets. The His214Asn would alter the cleavage dynamics of gamma–secretase from the disappeared interactions between His214 and Trp215 inside of the helix, resulting in elevated amyloid production. Hence, the increased Aβ was reflected in the increased Aβ oligomerization tendency and the accumulations of Aβ in the brain from amyloid-PET, leading to EOAD. |
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| language | English |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a24914f42458436e91f0a2d6a3efc5e82024-01-10T14:58:14ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-12-0125111610.3390/ijms25010116<i>PSEN1</i> His214Asn Mutation in a Korean Patient with Familial EOAD and the Importance of Histidine–Tryptophan Interactions in TM-4 StabilityEva Bagyinszky0Minju Kim1Young Ho Park2Seong Soo A. An3SangYun Kim4Department of Industrial and Environmental Engineering, Graduate School of Environment, Gachon University, Seongnam 13120, Republic of KoreaDepartment of Neurology, Seoul National University College of Medicine & Clinical Neuroscience Center, Seoul National University Bundang Hospital, Seongnam 13620, Republic of KoreaDepartment of Neurology, Seoul National University College of Medicine & Clinical Neuroscience Center, Seoul National University Bundang Hospital, Seongnam 13620, Republic of KoreaDepartment of Bionano Technology, Gachon Medical Research Institute, Gachon University, Seongnam 13120, Republic of KoreaDepartment of Neurology, Seoul National University College of Medicine & Clinical Neuroscience Center, Seoul National University Bundang Hospital, Seongnam 13620, Republic of KoreaA pathogenic mutation in presenilin-1 (<i>PSEN1</i>), His214Asn, was found in a male patient with memory decline at the age of 41 in Korea for the first time. The proband patient was associated with a positive family history from his father, paternal aunt, and paternal grandmother without genetic testing. He was diagnosed with early onset Alzheimer’s disease (EOAD). <i>PSEN1</i> His214Asn was initially reported in an Italian family, where the patient developed phenotypes similar to the current proband patient. Magnetic resonance imaging (MRI) scans revealed a mild hippocampal atrophy. The amyloid positron emission tomography (amyloid-PET) was positive, along with the positive test results of the increased amyloid ß (Aβ) oligomerization tendency with blood. The <i>PSEN1</i> His214 amino acid position plays a significant role in the gamma–secretase function, especially from three additional reported mutations in this residue: His214Asp, His214Tyr, and His214Arg. The structure prediction model revealed that PSEN1 protein His214 may interact with Trp215 of His-Trp cation-π interaction, and the mutations of His214 would destroy this interaction. The His-Trp cation-π interaction between His214 and Trp215 would play a crucial structural role in stabilizing the 4th transmembrane domain of PSEN1 protein, especially when aromatic residues were often reported in the membrane interface of the lipid–extracellular region of alpha helices or beta sheets. The His214Asn would alter the cleavage dynamics of gamma–secretase from the disappeared interactions between His214 and Trp215 inside of the helix, resulting in elevated amyloid production. Hence, the increased Aβ was reflected in the increased Aβ oligomerization tendency and the accumulations of Aβ in the brain from amyloid-PET, leading to EOAD.https://www.mdpi.com/1422-0067/25/1/116<i>PSEN1</i>early onset Alzheimer’s diseasemutationwhole-exome sequencing |
| spellingShingle | Eva Bagyinszky Minju Kim Young Ho Park Seong Soo A. An SangYun Kim <i>PSEN1</i> His214Asn Mutation in a Korean Patient with Familial EOAD and the Importance of Histidine–Tryptophan Interactions in TM-4 Stability International Journal of Molecular Sciences <i>PSEN1</i> early onset Alzheimer’s disease mutation whole-exome sequencing |
| title | <i>PSEN1</i> His214Asn Mutation in a Korean Patient with Familial EOAD and the Importance of Histidine–Tryptophan Interactions in TM-4 Stability |
| title_full | <i>PSEN1</i> His214Asn Mutation in a Korean Patient with Familial EOAD and the Importance of Histidine–Tryptophan Interactions in TM-4 Stability |
| title_fullStr | <i>PSEN1</i> His214Asn Mutation in a Korean Patient with Familial EOAD and the Importance of Histidine–Tryptophan Interactions in TM-4 Stability |
| title_full_unstemmed | <i>PSEN1</i> His214Asn Mutation in a Korean Patient with Familial EOAD and the Importance of Histidine–Tryptophan Interactions in TM-4 Stability |
| title_short | <i>PSEN1</i> His214Asn Mutation in a Korean Patient with Familial EOAD and the Importance of Histidine–Tryptophan Interactions in TM-4 Stability |
| title_sort | i psen1 i his214asn mutation in a korean patient with familial eoad and the importance of histidine tryptophan interactions in tm 4 stability |
| topic | <i>PSEN1</i> early onset Alzheimer’s disease mutation whole-exome sequencing |
| url | https://www.mdpi.com/1422-0067/25/1/116 |
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