| Literature DB >> 29656860 |
Hanyin Cheng1, Avinash V Dharmadhikari1, Sylvia Varland2, Ning Ma3, Deepti Domingo4, Robert Kleyner5, Alan F Rope6, Margaret Yoon5, Asbjørg Stray-Pedersen7, Jennifer E Posey8, Sarah R Crews9, Mohammad K Eldomery8, Zeynep Coban Akdemir8, Andrea M Lewis10, Vernon R Sutton8, Jill A Rosenfeld8, Erin Conboy11, Katherine Agre11, Fan Xia12, Magdalena Walkiewicz13, Mauro Longoni14, Frances A High15, Marjon A van Slegtenhorst16, Grazia M S Mancini16, Candice R Finnila17, Arie van Haeringen18, Nicolette den Hollander18, Claudia Ruivenkamp18, Sakkubai Naidu19, Sonal Mahida19, Elizabeth E Palmer20, Lucinda Murray21, Derek Lim22, Parul Jayakar23, Michael J Parker24, Stefania Giusto25, Emanuela Stracuzzi25, Corrado Romano25, Jennifer S Beighley26, Raphael A Bernier26, Sébastien Küry27, Mathilde Nizon27, Mark A Corbett28, Marie Shaw28, Alison Gardner28, Christopher Barnett29, Ruth Armstrong30, Karin S Kassahn31, Anke Van Dijck32, Geert Vandeweyer32, Tjitske Kleefstra33, Jolanda Schieving33, Marjolijn J Jongmans33, Bert B A de Vries33, Rolph Pfundt33, Bronwyn Kerr34, Samantha K Rojas35, Kym M Boycott35, Richard Person36, Rebecca Willaert36, Evan E Eichler37, R Frank Kooy32, Yaping Yang12, Joseph C Wu3, James R Lupski38, Thomas Arnesen39, Gregory M Cooper17, Wendy K Chung40, Jozef Gecz41, Holly A F Stessman9, Linyan Meng42, Gholson J Lyon43.
Abstract
N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.Entities:
Keywords: N-terminal acetylation (NTA); N-terminal acetyltransferases (NATs); NAA10; NAA15; NatA complex; Ogden syndrome; autism; congenital heart defects; intellectual disability; neurodevelopmental disorder
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Year: 2018 PMID： 29656860 PMCID： PMC5986698 DOI： 10.1016/j.ajhg.2018.03.004
Source DB: PubMed Journal: Am J Hum Genet ISSN： 0002-9297 Impact factor: 11.025