Boegershausen, Nina, Krawczyk, Hannah E., Jamra, Rami A., Lin, Sheng-Jia ORCID: 0000-0002-7559-6529, Yigit, Goekhan, Huening, Irina, Polo, Anna M., Vona, Barbara ORCID: 0000-0002-6719-3447, Huang, Kevin ORCID: 0000-0002-2512-7812, Schmidt, Julia, Altmueller, Janine, Luppe, Johannes, Platzer, Konrad, Doergeloh, Beate B., Busche, Andreas, Biskup, Saskia, Mendes, Marisa, I, Smith, Desiree E. C., Salomons, Gajja S., Zibat, Arne, Bueltmann, Eva, Nuernberg, Peter, Spielmann, Malte, Lemke, Johannes R., Li, Yun, Zenker, Martin, Varshney, Gaurav K. ORCID: 0000-0002-0429-1904, Hillen, Hauke S., Kratz, Christian P. and Wollnik, Bernd ORCID: 0000-0003-2589-0364 (2022). WARS1 and SARS1: Two tRNA synthetases implicated in autosomal recessive microcephaly. Hum. Mutat., 43 (10). S. 1454 - 1472. HOBOKEN: WILEY. ISSN 1098-1004

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Abstract

Aminoacylation of transfer RNA (tRNA) is a key step in protein biosynthesis, carried out by highly specific aminoacyl-tRNA synthetases (ARSs). ARSs have been implicated in autosomal dominant and autosomal recessive human disorders. Autosomal dominant variants in tryptophanyl-tRNA synthetase 1 (WARS1) are known to cause distal hereditary motor neuropathy and Charcot-Marie-Tooth disease, but a recessively inherited phenotype is yet to be clearly defined. Seryl-tRNA synthetase 1 (SARS1) has rarely been implicated in an autosomal recessive developmental disorder. Here, we report five individuals with biallelic missense variants in WARS1 or SARS1, who presented with an overlapping phenotype of microcephaly, developmental delay, intellectual disability, and brain anomalies. Structural mapping showed that the SARS1 variant is located directly within the enzyme's active site, most likely diminishing activity, while the WARS1 variant is located in the N-terminal domain. We further characterize the identified WARS1 variant by showing that it negatively impacts protein abundance and is unable to rescue the phenotype of a CRISPR/Cas9 wars1 knockout zebrafish model. In summary, we describe two overlapping autosomal recessive syndromes caused by variants in WARS1 and SARS1, present functional insights into the pathogenesis of the WARS1-related syndrome and define an emerging disease spectrum: ARS-related developmental disorders with or without microcephaly.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Boegershausen, NinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krawczyk, Hannah E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jamra, Rami A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lin, Sheng-JiaUNSPECIFIEDorcid.org/0000-0002-7559-6529UNSPECIFIED
Yigit, GoekhanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huening, IrinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Polo, Anna M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vona, BarbaraUNSPECIFIEDorcid.org/0000-0002-6719-3447UNSPECIFIED
Huang, KevinUNSPECIFIEDorcid.org/0000-0002-2512-7812UNSPECIFIED
Schmidt, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Luppe, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Platzer, KonradUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doergeloh, Beate B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Busche, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Biskup, SaskiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mendes, Marisa, IUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smith, Desiree E. C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Salomons, Gajja S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zibat, ArneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bueltmann, EvaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spielmann, MalteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lemke, Johannes R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, YunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zenker, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Varshney, Gaurav K.UNSPECIFIEDorcid.org/0000-0002-0429-1904UNSPECIFIED
Hillen, Hauke S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kratz, Christian P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wollnik, BerndUNSPECIFIEDorcid.org/0000-0003-2589-0364UNSPECIFIED
URN: urn:nbn:de:hbz:38-695647
DOI: 10.1002/humu.24430
Journal or Publication Title: Hum. Mutat.
Volume: 43
Number: 10
Page Range: S. 1454 - 1472
Date: 2022
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1098-1004
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
OF-FUNCTION; MUTATIONS CAUSE; RETARDATION; DISORDERS; VARIANTS; COMPLEX; ATROPHY; SERVER; ONSETMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69564

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