ELIZA

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308018 occurrences (No.72 in the rank) during 5 years in the PubMed. [cache]

29) A large number of SORL1 missense variants have been identified in AD patients, but their functional consequences remain largely undefined.

--- ABSTRACT ---

PMID:34922638 DOI:10.1186/s40478-021-01294-4

2021 Acta neuropathologica communications

* Impaired SorLA maturation and trafficking as a new mechanism for SORL1 missense variants in Alzheimer disease.

- The SorLA protein, encoded by the SORL1 gene, is a major player in Alzheimer's disease (AD) pathophysiology. Functional and genetic studies demonstrated that SorLA deficiency results in increased production of Aβ peptides, and thus a higher risk of AD. A large number of SORL1 missense variants have been identified in AD patients, but their functional consequences remain largely undefined. Here, we identified a new pathophysiological mechanism, by which rare SORL1 missense variants identified in AD patients result in altered maturation and trafficking of the SorLA protein. An initial screening, based on the overexpression of 70 SorLA variants in HEK293 cells, revealed that 15 of them (S114R, R332W, G543E, S564G, S577P, R654W, R729W, D806N, Y934C, D1535N, D1545E, P1654L, Y1816C, W1862C, P1914S) induced a maturation and trafficking-deficient phenotype. Three of these variants (R332W, S577P, and R654W) and two maturation-competent variants (S124R and N371T) were further studied in details in CRISPR/Cas9-modified hiPSCs. When expressed at endogenous levels, the R332W, S577P, and R654W SorLA variants also showed a maturation defective profile. We further demonstrated that these variants were largely retained in the endoplasmic reticulum, resulting in a reduction in the delivery of SorLA mature protein to the plasma membrane and to the endosomal system. Importantly, expression of the R332W and R654W variants in hiPSCs was associated with a clear increase of Aβ secretion, demonstrating a loss-of-function effect of these SorLA variants regarding this ultimate readout, and a direct link with AD pathophysiology. Furthermore, structural analysis of the impact of missense variants on SorLA protein suggested that impaired cellular trafficking of SorLA protein could be due to subtle variations of the protein 3D structure resulting from changes in the interatomic interactions.

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(1)389 of	(4)10 table	(7)3 is	(10)2 Sequencing
(2)19 and	(5)5 in	(8)3 variation
(3)18 table,	(6)3 null	(9)3 variations

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--- WordNet output for number --- =>に番号をつける, 数, 番号, 総数, 若干, 多数, 曲, 過ごす, 達する, 番号を唱える Overview of noun number The noun number has 11 senses (first 9 from tagged texts) 1. (131) number, figure -- (the property possessed by a sum or total or indefinite quantity of units or individuals; "he had a number of chores to do"; "the number of parameters is small"; "the figure was about a thousand") 2. (63) number -- (a concept of quantity involving zero and units; "every number has a unique position in the sequence") 3. (5) act, routine, number, turn, bit -- (a short theatrical performance that is part of a longer program; "he did his act three times every evening"; "she had a catchy little routine"; "it was one of the best numbers he ever did") 4. (5) phone number, telephone number, number -- (the number is used in calling a particular telephone; "he has an unlisted number") 5. (2) numeral, number -- (a symbol used to represent a number; "he learned to write the numerals before he went to school") 6. (2) issue, number -- (one of a series published periodically; "she found an old issue of the magazine in her dentist's waiting room") 7. (1) number -- (a select company of people; "I hope to become one of their number before I die") 8. (1) number, identification number -- (a numeral or string of numerals that is used for identification; "she refused to give them her Social Security number") 9. (1) number -- (a clothing measurement; "a number 13 shoe") 10. number -- (the grammatical category for the forms of nouns and pronouns and verbs that are used depending on the number of entities involved (singular or dual or plural); "in English the subject and the verb must agree in number") 11. number -- (an item of merchandise offered for sale; "she preferred the black nylon number"; "this sweater is an all-wool number") Overview of verb number The verb number has 6 senses (first 3 from tagged texts) 1. (6) total, number, add up, come, amount -- (add up in number or quantity; "The bills amounted to $2,000"; "The bill came to $2,000") 2. (2) number -- (give numbers to; "You should number the pages of the thesis") 3. (1) number, list -- (enumerate; "We must number the names of the great mathematicians") 4. count, number -- (put into a group; "The academy counts several Nobel Prize winners among its members") 5. count, number, enumerate, numerate -- (determine the number or amount of; "Can you count the books on your shelf?"; "Count your change") 6. number, keep down -- (place a limit on the number of) --- WordNet end ---