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Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice


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.

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.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
04 Faculty of Medicine > Institute of Medical Genetics
08 Research Priority Programs > Adaptive Brain Circuits in Development and Learning (AdaBD)
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Health Sciences > Multidisciplinary
Uncontrolled Keywords:Animals, Haploinsufficiency, Humans, Megalencephaly*, Methyltransferases / genetics, Mice, Knockout, Neurodevelopmental Disorders* / genetics, Phenotype, Methyltransferases
Language:English
Date:10 March 2023
Deposited On:21 Mar 2023 16:34
Last Modified:29 Apr 2024 01:36
Publisher:American Association for the Advancement of Science
ISSN:2375-2548
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1126/sciadv.ade1463
Related URLs:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10005179/ (Library Catalogue)
PubMed ID:36897941
Other Identification Number:PMCID: PMC10005179
Project Information:
  • : FunderUniversity of Zurich (UZH)
  • : Grant IDUniversity Research Priority Programs (URPP)
  • : Project TitleURPP Adaptive Brain Circuits in Development and Learning (AdaBD)
  • : Project Websitehttps://adabd.uzh.ch/
  • : FunderUniversity of Zurich (UZH)
  • : Grant IDUniversity Research Priority Programs (URPP)
  • : Project TitleURPP ITINERARE Innovative Therapies in Rare Diseases
  • : Project Websitehttps://www.itinerare.uzh.ch/
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)