Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function
<p dir="ltr">Aminoacyl-tRNA synthetases (ARSs) are essential enzymes for faithful assignment of amino acids to their cognate tRNA. Variants in ARS genes are frequently associated with clinically heterogeneous phenotypes in humans and follow both autosomal dominant or recessive inheri...
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| مؤلفون آخرون: | , , , , , , , , , , , , , , , , , , , , , , , |
| منشور في: |
2022
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إضافة وسم
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| _version_ | 1864513512359854080 |
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| author | Sheng‐Jia Lin (18877600) |
| author2 | Barbara Vona (5237843) Hillary M. Porter (18877603) Mahmoud Izadi (12899508) Kevin Huang (147764) Yves Lacassie (6034238) Jill A. Rosenfeld (9606199) Saadullah Khan (5735540) Cassidy Petree (17487198) Tayyiba A. Ali (18131836) Nazif Muhammad (15891860) Sher A. Khan (18877606) Noor Muhammad (820180) Pengfei Liu (136115) Marie‐Louise Haymon (18877609) Franz Rüschendorf (73756) Il‐Keun Kong (18877612) Linda Schnapp (18718837) Natasha Shur (18877615) Lynn Chorich (18877618) Lawrence Layman (3521192) Thomas Haaf (342924) Ehsan Pourkarimi (541179) Hyung‐Goo Kim (14776987) Gaurav K. Varshney (10671462) |
| author2_role | author author author author author author author author author author author author author author author author author author author author author author author author |
| author_facet | Sheng‐Jia Lin (18877600) Barbara Vona (5237843) Hillary M. Porter (18877603) Mahmoud Izadi (12899508) Kevin Huang (147764) Yves Lacassie (6034238) Jill A. Rosenfeld (9606199) Saadullah Khan (5735540) Cassidy Petree (17487198) Tayyiba A. Ali (18131836) Nazif Muhammad (15891860) Sher A. Khan (18877606) Noor Muhammad (820180) Pengfei Liu (136115) Marie‐Louise Haymon (18877609) Franz Rüschendorf (73756) Il‐Keun Kong (18877612) Linda Schnapp (18718837) Natasha Shur (18877615) Lynn Chorich (18877618) Lawrence Layman (3521192) Thomas Haaf (342924) Ehsan Pourkarimi (541179) Hyung‐Goo Kim (14776987) Gaurav K. Varshney (10671462) |
| author_role | author |
| dc.creator.none.fl_str_mv | Sheng‐Jia Lin (18877600) Barbara Vona (5237843) Hillary M. Porter (18877603) Mahmoud Izadi (12899508) Kevin Huang (147764) Yves Lacassie (6034238) Jill A. Rosenfeld (9606199) Saadullah Khan (5735540) Cassidy Petree (17487198) Tayyiba A. Ali (18131836) Nazif Muhammad (15891860) Sher A. Khan (18877606) Noor Muhammad (820180) Pengfei Liu (136115) Marie‐Louise Haymon (18877609) Franz Rüschendorf (73756) Il‐Keun Kong (18877612) Linda Schnapp (18718837) Natasha Shur (18877615) Lynn Chorich (18877618) Lawrence Layman (3521192) Thomas Haaf (342924) Ehsan Pourkarimi (541179) Hyung‐Goo Kim (14776987) Gaurav K. Varshney (10671462) |
| dc.date.none.fl_str_mv | 2022-07-11T06:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1002/humu.24435 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Biallelic_variants_in__i_WARS1_i__cause_a_highly_variable_neurodevelopmental_syndrome_and_implicate_a_critical_exon_for_normal_auditory_function/26095525 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Clinical sciences Neurosciences autosomal recessive biallelic variants C. elegans translation initiation sites tryptophanyl‐tRNA synthetase 1 (WARS1) WHEP domain zebrafish |
| dc.title.none.fl_str_mv | Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">Aminoacyl-tRNA synthetases (ARSs) are essential enzymes for faithful assignment of amino acids to their cognate tRNA. Variants in ARS genes are frequently associated with clinically heterogeneous phenotypes in humans and follow both autosomal dominant or recessive inheritance patterns in many instances. Variants in tryptophanyl-tRNA synthetase 1 (WARS1) cause autosomal dominantly inherited distal hereditary motor neuropathy and Charcot-Marie-Tooth disease. Presently, only one family with biallelic WARS1 variants has been described. We present three affected individuals from two families with biallelic variants (p.Met1? and p.(Asp419Asn)) in WARS1, showing varying severities of developmental delay and intellectual disability. Hearing impairment and microcephaly, as well as abnormalities of the brain, skeletal system, movement/gait, and behavior were variable features. Phenotyping of knocked down wars-1 in a Caenorhabditis elegans model showed depletion is associated with defects in germ cell development. A wars1 knockout vertebrate model recapitulates the human clinical phenotypes, confirms variant pathogenicity, and uncovers evidence implicating the p.Met1? variant as potentially impacting an exon critical for normal hearing. Together, our findings provide consolidating evidence for biallelic disruption of WARS1 as causal for an autosomal recessive neurodevelopmental syndrome and present a vertebrate model that recapitulates key phenotypes observed in patients.</p><h2>Other Information</h2><p dir="ltr">Published in: Human Mutation<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1002/humu.24435" target="_blank">https://dx.doi.org/10.1002/humu.24435</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_c88e81e33c047a622c7dee7a17f4b745 |
| identifier_str_mv | 10.1002/humu.24435 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/26095525 |
| publishDate | 2022 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory functionSheng‐Jia Lin (18877600)Barbara Vona (5237843)Hillary M. Porter (18877603)Mahmoud Izadi (12899508)Kevin Huang (147764)Yves Lacassie (6034238)Jill A. Rosenfeld (9606199)Saadullah Khan (5735540)Cassidy Petree (17487198)Tayyiba A. Ali (18131836)Nazif Muhammad (15891860)Sher A. Khan (18877606)Noor Muhammad (820180)Pengfei Liu (136115)Marie‐Louise Haymon (18877609)Franz Rüschendorf (73756)Il‐Keun Kong (18877612)Linda Schnapp (18718837)Natasha Shur (18877615)Lynn Chorich (18877618)Lawrence Layman (3521192)Thomas Haaf (342924)Ehsan Pourkarimi (541179)Hyung‐Goo Kim (14776987)Gaurav K. Varshney (10671462)Biomedical and clinical sciencesClinical sciencesNeurosciencesautosomal recessivebiallelic variantsC. eleganstranslation initiation sitestryptophanyl‐tRNA synthetase 1 (WARS1)WHEP domainzebrafish<p dir="ltr">Aminoacyl-tRNA synthetases (ARSs) are essential enzymes for faithful assignment of amino acids to their cognate tRNA. Variants in ARS genes are frequently associated with clinically heterogeneous phenotypes in humans and follow both autosomal dominant or recessive inheritance patterns in many instances. Variants in tryptophanyl-tRNA synthetase 1 (WARS1) cause autosomal dominantly inherited distal hereditary motor neuropathy and Charcot-Marie-Tooth disease. Presently, only one family with biallelic WARS1 variants has been described. We present three affected individuals from two families with biallelic variants (p.Met1? and p.(Asp419Asn)) in WARS1, showing varying severities of developmental delay and intellectual disability. Hearing impairment and microcephaly, as well as abnormalities of the brain, skeletal system, movement/gait, and behavior were variable features. Phenotyping of knocked down wars-1 in a Caenorhabditis elegans model showed depletion is associated with defects in germ cell development. A wars1 knockout vertebrate model recapitulates the human clinical phenotypes, confirms variant pathogenicity, and uncovers evidence implicating the p.Met1? variant as potentially impacting an exon critical for normal hearing. Together, our findings provide consolidating evidence for biallelic disruption of WARS1 as causal for an autosomal recessive neurodevelopmental syndrome and present a vertebrate model that recapitulates key phenotypes observed in patients.</p><h2>Other Information</h2><p dir="ltr">Published in: Human Mutation<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1002/humu.24435" target="_blank">https://dx.doi.org/10.1002/humu.24435</a></p>2022-07-11T06:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1002/humu.24435https://figshare.com/articles/journal_contribution/Biallelic_variants_in__i_WARS1_i__cause_a_highly_variable_neurodevelopmental_syndrome_and_implicate_a_critical_exon_for_normal_auditory_function/26095525CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/260955252022-07-11T06:00:00Z |
| spellingShingle | Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function Sheng‐Jia Lin (18877600) Biomedical and clinical sciences Clinical sciences Neurosciences autosomal recessive biallelic variants C. elegans translation initiation sites tryptophanyl‐tRNA synthetase 1 (WARS1) WHEP domain zebrafish |
| status_str | publishedVersion |
| title | Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function |
| title_full | Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function |
| title_fullStr | Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function |
| title_full_unstemmed | Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function |
| title_short | Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function |
| title_sort | Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function |
| topic | Biomedical and clinical sciences Clinical sciences Neurosciences autosomal recessive biallelic variants C. elegans translation initiation sites tryptophanyl‐tRNA synthetase 1 (WARS1) WHEP domain zebrafish |