TY  - JOUR
AU  - Hengel, Holger
AU  - Hannan, Shabab B
AU  - Dyack, Sarah
AU  - MacKay, Sara B
AU  - Schatz, Ulrich
AU  - Fleger, Martin
AU  - Kurringer, Andreas
AU  - Balousha, Ghassan
AU  - Ghanim, Zaid
AU  - Alkuraya, Fowzan S
AU  - Alzaidan, Hamad
AU  - Alsaif, Hessa S
AU  - Mitani, Tadahiro
AU  - Bozdogan, Sevcan
AU  - Pehlivan, Davut
AU  - Lupski, James R
AU  - Gleeson, Joseph J
AU  - Dehghani, Mohammadreza
AU  - Mehrjardi, Mohammad Y V
AU  - Sherr, Elliott H
AU  - Parks, Kendall C
AU  - Argilli, Emanuela
AU  - Begtrup, Amber
AU  - Galehdari, Hamid
AU  - Balousha, Osama
AU  - Shariati, Gholamreza
AU  - Mazaheri, Neda
AU  - Malamiri, Reza A
AU  - Pagnamenta, Alistair T
AU  - Kingston, Helen
AU  - Banka, Siddharth
AU  - Jackson, Adam
AU  - Osmond, Mathew
AU  - Rieß, Angelika
AU  - Haack, Tobias B
AU  - Nägele, Thomas
AU  - Schuster, Stefanie
AU  - Hauser, Stefan
AU  - Admard, Jakob
AU  - Casadei, Nicolas
AU  - Velic, Ana
AU  - Macek, Boris
AU  - Ossowski, Stephan
AU  - Houlden, Henry
AU  - Maroofian, Reza
AU  - Schöls, Ludger
TI  - Bi-allelic loss-of-function variants in BCAS3 cause a syndromic neurodevelopmental disorder.
JO  - The American journal of human genetics
VL  - 108
IS  - 6
SN  - 0002-9297
CY  - New York, NY
PB  - Elsevier
M1  - DZNE-2021-01048
SP  - 1069 - 1082
PY  - 2021
AB  - 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.
KW  - Adolescent
KW  - Adult
KW  - Animals
KW  - Cell Movement
KW  - Child
KW  - Child, Preschool
KW  - Drosophila
KW  - Female
KW  - Fibroblasts: metabolism
KW  - Fibroblasts: pathology
KW  - Humans
KW  - Infant
KW  - Loss of Function Mutation
KW  - Loss of Heterozygosity
KW  - Male
KW  - Mice
KW  - Mice, Knockout
KW  - Neoplasm Proteins: genetics
KW  - Neoplasm Proteins: metabolism
KW  - Neurodevelopmental Disorders: etiology
KW  - Neurodevelopmental Disorders: metabolism
KW  - Neurodevelopmental Disorders: pathology
KW  - Pedigree
KW  - Proteome: analysis
KW  - Young Adult
KW  - BCAS3 (Other)
KW  - UAS-Gal4 (Other)
KW  - fibroblasts (Other)
KW  - global developmental delay (Other)
KW  - microcephaly (Other)
KW  - neurodevelopmental disorder (Other)
KW  - proteomics (Other)
KW  - pyramidal tract involvement (Other)
KW  - thin corpus callosum (Other)
KW  - transcriptomics (Other)
KW  - BCAS3 protein, human (NLM Chemicals)
KW  - Neoplasm Proteins (NLM Chemicals)
KW  - Proteome (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:34022130
C2  - pmc:PMC8206390
DO  - DOI:10.1016/j.ajhg.2021.04.024
UR  - https://pub.dzne.de/record/155888
ER  -