De novo heterozygous missense and loss-of-function variants in CDC42BPB are associated with a neurodevelopmental phenotype.
Adolescent
Adult
Amino Acid Sequence
Autistic Disorder
/ epidemiology
Child
Child, Preschool
Developmental Disabilities
/ epidemiology
Female
Frameshift Mutation
Haploinsufficiency
Heterozygote
Humans
Infant
Infant, Newborn
Intellectual Disability
/ epidemiology
Loss of Function Mutation
/ genetics
Male
Mutation, Missense
/ genetics
Myotonin-Protein Kinase
/ genetics
Neurodevelopmental Disorders
/ epidemiology
Phenotype
CDC42BPB
MRCKβ
brain abnormalities
exome sequencing
neurodevelopmental disorder
Journal
American journal of medical genetics. Part A
ISSN: 1552-4833
Titre abrégé: Am J Med Genet A
Pays: United States
ID NLM: 101235741
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
08
10
2019
revised:
30
12
2019
accepted:
12
01
2020
pubmed:
8
2
2020
medline:
13
1
2021
entrez:
8
2
2020
Statut:
ppublish
Résumé
CDC42BPB encodes MRCKβ (myotonic dystrophy-related Cdc42-binding kinase beta), a serine/threonine protein kinase, and a downstream effector of CDC42, which has recently been associated with Takenouchi-Kosaki syndrome, an autosomal dominant neurodevelopmental disorder. We identified 12 heterozygous predicted deleterious variants in CDC42BPB (9 missense, 2 frameshift, and 1 nonsense) in 14 unrelated individuals (confirmed de novo in 11/14) with neurodevelopmental disorders including developmental delay/intellectual disability, autism, hypotonia, and structural brain abnormalities including cerebellar vermis hypoplasia and agenesis/hypoplasia of the corpus callosum. The frameshift and nonsense variants in CDC42BPB are expected to be gene-disrupting and lead to haploinsufficiency via nonsense-mediated decay. All missense variants are located in highly conserved and functionally important protein domains/regions: 3 are found in the protein kinase domain, 2 are in the citron homology domain, and 4 in a 20-amino acid sequence between 2 coiled-coil regions, 2 of which are recurrent. Future studies will help to delineate the natural history and to elucidate the underlying biological mechanisms of the missense variants leading to the neurodevelopmental and behavioral phenotypes.
Identifiants
pubmed: 32031333
doi: 10.1002/ajmg.a.61505
doi:
Substances chimiques
CDC42BPB protein, human
EC 2.7.1.-
Myotonin-Protein Kinase
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
962-973Informations de copyright
© 2020 Wiley Periodicals, Inc.
Références
Deciphering Developmental Disorders Study. (2017a). Prevalence and architecture of de novo mutations in developmental disorders. Nature, 542(7642), 433-438. https://doi.org/10.1038/nature21062
Dulovic-Mahlow, M., Trinh, J., Kandaswamy, K. K., Braathen, G. J., Di Donato, N., Rahikkala, E., … Lohmann, K. (2019). De novo variants in TAOK1 cause neurodevelopmental disorders. American Journal of Human Genetics, 105(1), 213-220. https://doi.org/10.1016/j.ajhg.2019.05.005
Gussow, A. B., Petrovski, S., Wang, Q., Allen, A. S., & Goldstein, D. B. (2016). The intolerance to functional genetic variation of protein domains predicts the localization of pathogenic mutations within genes. Genome Biology, 17, 9. https://doi.org/10.1186/s13059-016-0869-4
Heikkila, T., Wheatley, E., Crighton, D., Schroder, E., Boakes, A., Kaye, S. J., … Olson, M. F. (2011). Co-crystal structures of inhibitors with MRCKbeta, a key regulator of tumor cell invasion. PLoS One, 6(9), e24825. https://doi.org/10.1371/journal.pone.0024825
Hiatt, S. M., Thompson, M. L., Prokop, J. W., Lawlor, J. M. J., Gray, D. E., Bebin, E. M., … Cooper, G. M. (2019). Deleterious variation in BRSK2 associates with a neurodevelopmental disorder. American Journal of Human Genetics, 104(4), 701-708. https://doi.org/10.1016/j.ajhg.2019.02.002
Karczewski, K. J., Francioli, L. C., Tiao, G., Cummings, B. B., Alföldi, J., Wang, Q., … MacArthur, D. G. (2019). Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes. bioRxiv, 531210. https://doi.org/10.1101/531210
Kitagishi, Y., Minami, A., Nakanishi, A., Ogura, Y., & Matsuda, S. (2015). Neuron membrane trafficking and protein kinases involved in autism and ADHD. International Journal of Molecular Sciences, 16(2), 3095-3115. https://doi.org/10.3390/ijms16023095
Martinelli, S., Krumbach, O. H. F., Pantaleoni, F., Coppola, S., Amin, E., Pannone, L., … Mirzaa, G. M. (2018). Functional dysregulation of CDC42 causes diverse developmental phenotypes. American Journal of Human Genetics, 102(2), 309-320. https://doi.org/10.1016/j.ajhg.2017.12.015
Moncrieff, C. L., Bailey, M. E., Morrison, N., & Johnson, K. J. (1999). Cloning and chromosomal localization of human Cdc42-binding protein kinase beta. Genomics, 57(2), 297-300. https://doi.org/10.1006/geno.1999.5769
O'Roak, B. J., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B. P., … Eichler, E. E. (2012). Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature, 485(7397), 246-250. https://doi.org/10.1038/nature10989
Papatheodorou, I., Fonseca, N. A., Keays, M., Tang, Y. A., Barrera, E., Bazant, W., … Petryszak, R. (2018). Expression atlas: Gene and protein expression across multiple studies and organisms. Nucleic Acids Research, 46(D1), D246-d251. https://doi.org/10.1093/nar/gkx1158
Sobreira, N., Schiettecatte, F., Valle, D., & Hamosh, A. (2015). GeneMatcher: A matching tool for connecting investigators with an interest in the same gene. Human Mutation, 36(10), 928-930. https://doi.org/10.1002/humu.22844
Takenouchi, T., Kosaki, R., Niizuma, T., Hata, K., & Kosaki, K. (2015). Macrothrombocytopenia and developmental delay with a de novo CDC42 mutation: Yet another locus for thrombocytopenia and developmental delay. Am J Med Genet A, 167a(11), 2822-2825. https://doi.org/10.1002/ajmg.a.37275
Takenouchi, T., Okamoto, N., Ida, S., Uehara, T., & Kosaki, K. (2016). Further evidence of a mutation in CDC42 as a cause of a recognizable syndromic form of thrombocytopenia. Am J Med Genet A, 170a(4), 852-855. https://doi.org/10.1002/ajmg.a.37526
Unbekandt, M., & Olson, M. F. (2014). The actin-myosin regulatory MRCK kinases: Regulation, biological functions and associations with human cancer. Journal of Molecular Medicine (Berlin, Germany), 92(3), 217-225. https://doi.org/10.1007/s00109-014-1133-6