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Identification and characterization of novel and rare susceptible variants in Indian amyotrophic lateral sclerosis patients
Rare missense variants play a crucial role in amyotrophic lateral sclerosis (ALS) pathophysiology. We report rare/novel missense variants from 154 Indian ALS patients, identified through targeted sequencing of 25 ALS-associated genes. As pathogenic variants could explain only a small percentage of A...
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| Published in: | Neurogenetics 2019-10, Vol.20 (4), p.197-208 |
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| Main Authors: | , , , , , , |
| Format: | Article |
| Language: | English |
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| container_end_page | 208 |
| container_issue | 4 |
| container_start_page | 197 |
| container_title | Neurogenetics |
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| creator | Narain, Priyam Padhi, Aditya K. Dave, Upma Mishra, Dibyakanti Bhatia, Rohit Vivekanandan, Perumal Gomes, James |
| description | Rare missense variants play a crucial role in amyotrophic lateral sclerosis (ALS) pathophysiology. We report rare/novel missense variants from 154 Indian ALS patients, identified through targeted sequencing of 25 ALS-associated genes. As pathogenic variants could explain only a small percentage of ALS pathophysiology in our cohort, we investigated the frequency of tolerated and benign novel/rare variants, which could be potentially ALS susceptible. These variants were identified in 5.36% (8/149) of sporadic ALS (sALS) cases; with one novel variant each in
ERBB4
,
SETX
,
DCTN1
, and
MATR3
; four rare variants, one each in
PON2
and
ANG
and two different rare variants in
SETX
. Identified variants were either absent or present at extremely rare frequencies (MAF |
| doi_str_mv | 10.1007/s10048-019-00584-3 |
| format | article |
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ERBB4
,
SETX
,
DCTN1
, and
MATR3
; four rare variants, one each in
PON2
and
ANG
and two different rare variants in
SETX
. Identified variants were either absent or present at extremely rare frequencies (MAF < 0.01) in large population databases and were absent in 50 healthy controls sequenced through Sanger method. Furthermore, an oligogenic basis of ALS was observed in three sALS, with co-occurrence of intermediate-length repeat expansions in
ATXN2
and a rare/novel variant in
DCTN1
and
SETX
genes. Additionally, molecular dynamics and biochemical functional analysis of an angiogenin variant (R21G) identified from our cohort demonstrated loss of ribonucleolytic and nuclear translocation activities. Our findings suggest that rare variants could be potentially pathogenic and functional studies are warranted to decisively establish the pathogenic mechanisms associated with them.</description><identifier>ISSN: 1364-6745</identifier><identifier>EISSN: 1364-6753</identifier><identifier>DOI: 10.1007/s10048-019-00584-3</identifier><identifier>PMID: 31432357</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Amyotrophic lateral sclerosis ; Angiogenin ; Biomedical and Life Sciences ; Biomedicine ; ErbB-2 protein ; Human Genetics ; Molecular Medicine ; Neurosciences ; Nuclear transport ; Original Article</subject><ispartof>Neurogenetics, 2019-10, Vol.20 (4), p.197-208</ispartof><rights>Springer-Verlag GmbH Germany, part of Springer Nature 2019</rights><rights>neurogenetics is a copyright of Springer, (2019). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c375t-90acefb1ce91ce79ed01ab4e461e02840d742c76cb951a640998a1eb65c131353</citedby><cites>FETCH-LOGICAL-c375t-90acefb1ce91ce79ed01ab4e461e02840d742c76cb951a640998a1eb65c131353</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31432357$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Narain, Priyam</creatorcontrib><creatorcontrib>Padhi, Aditya K.</creatorcontrib><creatorcontrib>Dave, Upma</creatorcontrib><creatorcontrib>Mishra, Dibyakanti</creatorcontrib><creatorcontrib>Bhatia, Rohit</creatorcontrib><creatorcontrib>Vivekanandan, Perumal</creatorcontrib><creatorcontrib>Gomes, James</creatorcontrib><title>Identification and characterization of novel and rare susceptible variants in Indian amyotrophic lateral sclerosis patients</title><title>Neurogenetics</title><addtitle>Neurogenetics</addtitle><addtitle>Neurogenetics</addtitle><description>Rare missense variants play a crucial role in amyotrophic lateral sclerosis (ALS) pathophysiology. We report rare/novel missense variants from 154 Indian ALS patients, identified through targeted sequencing of 25 ALS-associated genes. As pathogenic variants could explain only a small percentage of ALS pathophysiology in our cohort, we investigated the frequency of tolerated and benign novel/rare variants, which could be potentially ALS susceptible. These variants were identified in 5.36% (8/149) of sporadic ALS (sALS) cases; with one novel variant each in
ERBB4
,
SETX
,
DCTN1
, and
MATR3
; four rare variants, one each in
PON2
and
ANG
and two different rare variants in
SETX
. Identified variants were either absent or present at extremely rare frequencies (MAF < 0.01) in large population databases and were absent in 50 healthy controls sequenced through Sanger method. Furthermore, an oligogenic basis of ALS was observed in three sALS, with co-occurrence of intermediate-length repeat expansions in
ATXN2
and a rare/novel variant in
DCTN1
and
SETX
genes. Additionally, molecular dynamics and biochemical functional analysis of an angiogenin variant (R21G) identified from our cohort demonstrated loss of ribonucleolytic and nuclear translocation activities. Our findings suggest that rare variants could be potentially pathogenic and functional studies are warranted to decisively establish the pathogenic mechanisms associated with them.</description><subject>Amyotrophic lateral sclerosis</subject><subject>Angiogenin</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>ErbB-2 protein</subject><subject>Human Genetics</subject><subject>Molecular Medicine</subject><subject>Neurosciences</subject><subject>Nuclear transport</subject><subject>Original Article</subject><issn>1364-6745</issn><issn>1364-6753</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNp9kU9PFjEQxhujEQS_gAfThAuX1Xb7b3skBPRNSLzIuZntzkrJvu3S7pKgX97KIiQePLSdzPzmmWkeQj5w9okzZj6XesuuYdw2jKlONuIVOeRCy0YbJV4_x1IdkHel3DLGjRbdW3IguBStUOaQ_NoNGJcwBg9LSJFCHKi_gQx-wRx-bsk00pjucXqsZshIy1o8zkvoJ6T3kAPEpdAQ6S4ONaawf0hLTvNN8HSCqgQTLX7CnEoodK6qdWg5Jm9GmAq-f3qPyPXlxffzr83Vty-787OrxgujlsYy8Dj23KOtx1gcGIdeotQcWdtJNhjZeqN9bxUHLZm1HXDstfJccKHEETnddOec7lYsi9uHuv40QcS0Fte2VkljulZW9OQf9DatOdbtKmW0tkIoXal2o3z9UMk4ujmHPeQHx5n7Y43brHHVGvdojRO16eOT9NrvcXhu-etFBcQGlFqKPzC_zP6P7G8xZ5uA</recordid><startdate>20191001</startdate><enddate>20191001</enddate><creator>Narain, Priyam</creator><creator>Padhi, Aditya K.</creator><creator>Dave, Upma</creator><creator>Mishra, Dibyakanti</creator><creator>Bhatia, Rohit</creator><creator>Vivekanandan, Perumal</creator><creator>Gomes, James</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88G</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PSYQQ</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20191001</creationdate><title>Identification and characterization of novel and rare susceptible variants in Indian amyotrophic lateral sclerosis patients</title><author>Narain, Priyam ; 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We report rare/novel missense variants from 154 Indian ALS patients, identified through targeted sequencing of 25 ALS-associated genes. As pathogenic variants could explain only a small percentage of ALS pathophysiology in our cohort, we investigated the frequency of tolerated and benign novel/rare variants, which could be potentially ALS susceptible. These variants were identified in 5.36% (8/149) of sporadic ALS (sALS) cases; with one novel variant each in
ERBB4
,
SETX
,
DCTN1
, and
MATR3
; four rare variants, one each in
PON2
and
ANG
and two different rare variants in
SETX
. Identified variants were either absent or present at extremely rare frequencies (MAF < 0.01) in large population databases and were absent in 50 healthy controls sequenced through Sanger method. Furthermore, an oligogenic basis of ALS was observed in three sALS, with co-occurrence of intermediate-length repeat expansions in
ATXN2
and a rare/novel variant in
DCTN1
and
SETX
genes. Additionally, molecular dynamics and biochemical functional analysis of an angiogenin variant (R21G) identified from our cohort demonstrated loss of ribonucleolytic and nuclear translocation activities. Our findings suggest that rare variants could be potentially pathogenic and functional studies are warranted to decisively establish the pathogenic mechanisms associated with them.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>31432357</pmid><doi>10.1007/s10048-019-00584-3</doi><tpages>12</tpages></addata></record> |
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| issn | 1364-6745 1364-6753 |
| language | eng |
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| source | Springer Link |
| subjects | Amyotrophic lateral sclerosis Angiogenin Biomedical and Life Sciences Biomedicine ErbB-2 protein Human Genetics Molecular Medicine Neurosciences Nuclear transport Original Article |
| title | Identification and characterization of novel and rare susceptible variants in Indian amyotrophic lateral sclerosis patients |
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