Journal Article

DZNE-2021-01048

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Bi-allelic loss-of-function variants in BCAS3 cause a syndromic neurodevelopmental disorder.

Hengel, H. (First author)DZNE* ; Hannan, S. B.DZNE* ; Dyack, S. ; MacKay, S. B. ; Schatz, U. ; Fleger, M. ; Kurringer, A. ; Balousha, G. ; Ghanim, Z. ; Alkuraya, F. S. ; Alzaidan, H. ; Alsaif, H. S. ; Mitani, T. ; Bozdogan, S. ; Pehlivan, D. ; Lupski, J. R. ; Gleeson, J. J. ; Dehghani, M. ; Mehrjardi, M. Y. V. ; Sherr, E. H. ; Parks, K. C. ; Argilli, E. ; Begtrup, A. ; Galehdari, H. ; Balousha, O. ; Shariati, G. ; Mazaheri, N. ; Malamiri, R. A. ; Pagnamenta, A. T. ; Kingston, H. ; Banka, S. ; Jackson, A. ; Osmond, M. ; Consortium, C. C. (Collaboration Author) ; Consortium, G. E. R. (Collaboration Author) ; Rieß, A. ; Haack, T. B. ; Nägele, T. ; Schuster, S.DZNE* ; Hauser, S.DZNE* ; Admard, J. ; Casadei, N. ; Velic, A. ; Macek, B. ; Ossowski, S. ; Houlden, H. ; Maroofian, R. ; Schöls, L. (Last author)DZNE*

2021
Elsevier New York, NY

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Please use a persistent id in citations: doi:10.1016/j.ajhg.2021.04.024

Abstract: BCAS3 microtubule-associated cell migration factor (BCAS3) is a large, highly conserved cytoskeletal protein previously proposed to be critical in angiogenesis and implicated in human embryogenesis and tumorigenesis. Here, we established BCAS3 loss-of-function variants as causative for a neurodevelopmental disorder. We report 15 individuals from eight unrelated families with germline bi-allelic loss-of-function variants in BCAS3. All probands share a global developmental delay accompanied by pyramidal tract involvement, microcephaly, short stature, strabismus, dysmorphic facial features, and seizures. The human phenotype is less severe compared with the Bcas3 knockout mouse model and cannot be explained by angiogenic defects alone. Consistent with being loss-of-function alleles, we observed absence of BCAS3 in probands' primary fibroblasts. By comparing the transcriptomic and proteomic data based on probands' fibroblasts with those of the knockout mouse model, we identified similar dysregulated pathways resulting from over-representation analysis, while the dysregulation of some proposed key interactors could not be confirmed. Together with the results from a tissue-specific Drosophila loss-of-function model, we demonstrate a vital role for BCAS3 in neural tissue development.

Keyword(s): Adolescent (MeSH) ; Adult (MeSH) ; Animals (MeSH) ; Cell Movement (MeSH) ; Child (MeSH) ; Child, Preschool (MeSH) ; Drosophila (MeSH) ; Female (MeSH) ; Fibroblasts: metabolism (MeSH) ; Fibroblasts: pathology (MeSH) ; Humans (MeSH) ; Infant (MeSH) ; Loss of Function Mutation (MeSH) ; Loss of Heterozygosity (MeSH) ; Male (MeSH) ; Mice (MeSH) ; Mice, Knockout (MeSH) ; Neoplasm Proteins: genetics (MeSH) ; Neoplasm Proteins: metabolism (MeSH) ; Neurodevelopmental Disorders: etiology (MeSH) ; Neurodevelopmental Disorders: metabolism (MeSH) ; Neurodevelopmental Disorders: pathology (MeSH) ; Pedigree (MeSH) ; Proteome: analysis (MeSH) ; Young Adult (MeSH) ; BCAS3 ; UAS-Gal4 ; fibroblasts ; global developmental delay ; microcephaly ; neurodevelopmental disorder ; proteomics ; pyramidal tract involvement ; thin corpus callosum ; transcriptomics ; BCAS3 protein, human ; Neoplasm Proteins ; Proteome

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Contributing Institute(s):

1. Parkinson Genetics (AG Gasser)
2. Clinical Neurogenetics (AG Schöls)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2021

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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