Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice

Sarah E Sheppard, Laura Bryant, Rochelle N Wickramasekara, Courtney Vaccaro, Brynn Robertson, Jodi Hallgren, Jason Hulen, Cynthia J Watson, Victor Faundes, Yannis Duffourd, Pearl Lee, M Celeste Simon, Xavier de la Cruz, Natália Padilla, Marco Flores-Mendez, Naiara Akizu, Jacqueline Smiler, Renata Pellegrino Da Silva, Dong Li, Michael MarchAbdias Diaz-Rosado, Isabella Peixoto de Barcelos, Zhao Xiang Choa, Chin Yan Lim, Christèle Dubourg, Hubert Journel, Florence Demurger, Maureen Mulhern, Cigdem Akman, Natalie Lippa, Marisa Andrews, Dustin Baldridge, John Constantino, Arie van Haeringen, Irina Snoeck-Streef, Penny Chow, Anne Hing, John M Graham, Margaret Au, Laurence Faivre, Wei Shen, Rong Mao, Janice Palumbos, David Viskochil, William Gahl, Cynthia Tifft, Ellen Macnamara, Natalie Hauser, Rebecca Miller, Jessica Maffeo, Alexandra Afenjar, Diane Doummar, Boris Keren, Pamela Arn, Sarah Macklin-Mantia, Ilse Meerschaut, Bert Callewaert, André Reis, Christiane Zweier, Carole Brewer, Anand Saggar, Marie F Smeland, Ajith Kumar, Frances Elmslie, Charu Deshpande, Mathilde Nizon, Benjamin Cogne, Yvette van Ierland, Martina Wilke, Marjon van Slegtenhorst, Suzanne Koudijs, Jin Yun Chen, David Dredge, Danielle Pier, Saskia Wortmann, Erik-Jan Kamsteeg, Johannes Koch, Devon Haynes, Lynda Pollack, Hannah Titheradge, Kara Ranguin, Anne-Sophie Denommé-Pichon, Sacha Weber, Rubén Pérez de la Fuente, Jaime Sánchez Del Pozo, Jose Miguel Lezana Rosales, Pascal Joset, Katharina Steindl, Anita Rauch, Davide Mei, Francesco Mari, Renzo Guerrini, James Lespinasse, Frédéric Tran Mau-Them, Christophe Philippe, Benjamin Dauriat, Laure Raymond, Sébastien Moutton, Anna M Cueto-González, Tiong Yang Tan, Cyril Mignot, Sarah Grotto, Florence Renaldo, Theodore G Drivas, Laura Hennessy, Anna Raper, Ilaria Parenti, Frank J Kaiser, Alma Kuechler, Øyvind L Busk, Lily Islam, Jacob A Siedlik, Lindsay B Henderson, Jane Juusola, Richard Person, Rhonda E Schnur, Antonio Vitobello, Siddharth Banka, Elizabeth J Bhoj, Holly A F Stessman

Research output: Contribution to journalArticlepeer-review

Abstract

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.

Original languageEnglish
Article numbereade1463
Number of pages16
JournalScience Advances
Volume9
Issue number10
DOIs
Publication statusPublished - Mar 2023

Bibliographical note

Publisher Copyright:
© 2023 American Association for the Advancement of Science. All rights reserved.

Keywords

  • Animals
  • Humans
  • Mice
  • Haploinsufficiency
  • Megalencephaly
  • Methyltransferases/genetics
  • Mice, Knockout
  • Neurodevelopmental Disorders/genetics
  • Phenotype

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