Scala, Marcello ORCID: 0000-0003-2194-7239, Drouot, Nathalie, MacLennan, Suzanna C., Wessels, Marja W., Krygier, Magdalena, Pavinato, Lisa ORCID: 0000-0002-7630-8365, Telegrafi, Aida, de Man, Stella A., van Slegtenhorst, Marjon, Iacomino, Michele ORCID: 0000-0003-4788-9719, Madia, Francesca, Scudieri, Paolo, Uva, Paolo ORCID: 0000-0002-9524-8492, Giacomini, Thea, Nobile, Giulia, Mancardi, Maria Margherita, Balagura, Ganna ORCID: 0000-0003-0212-8318, Galloni, Giovanni Battista, Verrotti, Alberto, Umair, Muhammad, Khan, Amjad, Liebelt, Jan, Schmidts, Miriam, Langer, Thorsten, Brusco, Alfredo ORCID: 0000-0002-8318-7231, Lipska-Zietkiewicz, Beata S., Saris, Jasper J., Charlet-Berguerand, Nicolas ORCID: 0000-0002-4423-4920, Zara, Federico, Striano, Pasquale and Piton, Amelie (2022). De novo truncating NOVA2 variants affect alternative splicing and lead to heterogeneous neurodevelopmental phenotypes. Hum. Mutat., 43 (9). S. 1299 - 1314. HOBOKEN: WILEY. ISSN 1098-1004

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Abstract

Alternative splicing (AS) is crucial for cell-type-specific gene transcription and plays a critical role in neuronal differentiation and synaptic plasticity. De novo frameshift variants in NOVA2, encoding a neuron-specific key splicing factor, have been recently associated with a new neurodevelopmental disorder (NDD) with hypotonia, neurological features, and brain abnormalities. We investigated eight unrelated individuals by exome sequencing (ES) and identified seven novel pathogenic NOVA2 variants, including two with a novel localization at the KH1 and KH3 domains. In addition to a severe NDD phenotype, novel clinical features included psychomotor regression, attention deficit-hyperactivity disorder (ADHD), dyspraxia, and urogenital and endocrinological manifestations. To test the effect of the variants on splicing regulation, we transfected HeLa cells with wildtype and mutant NOVA2 complementary DNA (cDNA). The novel variants NM_002516.4:c.754_756delCTGinsTT p.(Leu252Phefs*144) and c.1329dup p.(Lys444Glnfs*82) all negatively affected AS events. The distal p.(Lys444Glnfs*82) variant, causing a partial removal of the KH3 domain, had a milder functional effect leading to an intermediate phenotype. Our findings expand the molecular and phenotypic spectrum of NOVA2-related NDD, supporting the pathogenic role of AS disruption by truncating variants and suggesting that this is a heterogeneous condition with variable clinical course.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Scala, MarcelloUNSPECIFIEDorcid.org/0000-0003-2194-7239UNSPECIFIED
Drouot, NathalieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
MacLennan, Suzanna C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wessels, Marja W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krygier, MagdalenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pavinato, LisaUNSPECIFIEDorcid.org/0000-0002-7630-8365UNSPECIFIED
Telegrafi, AidaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Man, Stella A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Slegtenhorst, MarjonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Iacomino, MicheleUNSPECIFIEDorcid.org/0000-0003-4788-9719UNSPECIFIED
Madia, FrancescaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scudieri, PaoloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Uva, PaoloUNSPECIFIEDorcid.org/0000-0002-9524-8492UNSPECIFIED
Giacomini, TheaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nobile, GiuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mancardi, Maria MargheritaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Balagura, GannaUNSPECIFIEDorcid.org/0000-0003-0212-8318UNSPECIFIED
Galloni, Giovanni BattistaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Verrotti, AlbertoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Umair, MuhammadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khan, AmjadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liebelt, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidts, MiriamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Langer, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brusco, AlfredoUNSPECIFIEDorcid.org/0000-0002-8318-7231UNSPECIFIED
Lipska-Zietkiewicz, Beata S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saris, Jasper J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Charlet-Berguerand, NicolasUNSPECIFIEDorcid.org/0000-0002-4423-4920UNSPECIFIED
Zara, FedericoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Striano, PasqualeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Piton, AmelieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-697083
DOI: 10.1002/humu.24414
Journal or Publication Title: Hum. Mutat.
Volume: 43
Number: 9
Page Range: S. 1299 - 1314
Date: 2022
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1098-1004
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
NONSENSE MUTATIONS; SEQUENCE VARIANTS; CIRCULAR RNAS; MECHANISMS; EXPRESSION; INSIGHTS; BINDINGMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69708

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