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Asif, M.* ; Khayyat, A.I.A.* ; Alawbathani, S.* ; Abdullah, U.* ; Sanner, A.* ; Georgomanolis, T.* ; Haasters, J.* ; Becker, K.* ; Budde, B.* ; Becker, C.* ; Thiele, H.* ; Baig, S.M.* ; Isidoro-García, M.* ; Winter, D.* ; Pogoda, H.M.* ; Muhammad, S.* ; Hammerschmidt, M.* ; Kraft, F.* ; Kurth, I.* ; Martin, H.G.* ; Wagner, M. ; Nürnberg, P.* ; Hussain, M.S.*

Biallelic loss-of-function variants of ZFTRAF1 cause neurodevelopmental disorder with microcephaly and hypotonia.

Genet. Med. 26:101143 (2024)
DOI PMC
Creative Commons Lizenzvertrag
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
PURPOSE: Neurodevelopmental disorders exhibit clinical and genetic heterogeneity, ergo manifest dysfunction in components of diverse cellular pathways; the precise pathomechanism for the majority remains elusive. METHODS: We studied five affected individuals from three unrelated families manifesting global developmental delay, postnatal microcephaly, and hypotonia. We employed exome sequencing and prioritized variants that were subsequently characterized using immunofluorescence, immunoblotting, pulldown assays, and RNA sequencing. RESULTS: We identified biallelic variants in ZFTRAF1, encoding a protein of yet unknown function. Four affected individuals from two unrelated families segregated two homozygous frameshift variants in ZFTRAF1, whereas, in the third family, an intronic splice site variant was detected. We investigated ZFTRAF1 at the cellular level and signified it as a nucleocytoplasmic protein in different human cell lines. ZFTRAF1 was completely absent in the fibroblasts of two affected individuals. We also identified 110 interacting proteins enriched in mRNA processing and autophagy-related pathways. Based on profiling of autophagy markers, patient-derived fibroblasts show irregularities in the protein degradation process. CONCLUSION: Thus, our findings suggest that biallelic variants of ZFTRAF1 cause a severe neurodevelopmental disorder.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Cyhr1 ; Neurodevelopmental Disorders ; Zftraf1 ; Autophagy ; Mrna-processing; Damaged Lysosomes; Autophagy; Proteins; Galectin-3; Cysteine; Family; Rich
ISSN (print) / ISBN 1530-0366
e-ISSN 1098-3600
Zeitschrift Genetics in Medicine
Quellenangaben Band: 26, Heft: 7, Seiten: , Artikelnummer: 101143 Supplement: ,
Verlag Lippincott Williams & Wilkins
Verlagsort Baltimore, Md.
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
Förderungen DFG Research Unit
Hertie Foundation
Koeln Fortune Program (Faculty of Medicine, University of Cologne)
Center for Molecular Medicine Cologne