PXD044735

PXD044735 is an original dataset announced via ProteomeXchange.

Title	Biallelic loss-of-function variants of ZFTRAF1 cause neurodevelopmental disorder with microcephaly and hypotonia by impairing autophagy
Description	Neurodevelopmental disorders have great clinical and genetic heterogeneity and are known to arise from dysfunction in components of diverse cellular pathways, the precise pathomechanism for the majority however remains elusive. We studied five patients from three unrelated families originating from Yemen, Germany and Spain. The affected individuals manifested global developmental delay, variable degrees of microcephaly and hypotonia. Whole exome sequencing identified biallelic variants in the ZFTRAF1, encoding a protein of unknown function. The four patients from two unrelated families segregated two homozygous frameshift variants, NM_001330618.2:c.1085_1086delTT;p.(Phe362Cysfs*18), NM_001330618.2:c.1162_1163delCT;p.(Leu388Glyfs*49) whereas the third family carried an intronic variant NM_001330618.2:c.612-2A>C;p.(?). We studied this protein at the cellular level and show that endogenous ZFTRAF1 is a nucleocytoplasmic protein with predominant nuclear expression in different human cell lines. We also investigated ZFTRAF1 interactome by pulldown assay and identified 110 interacting proteins that are the crucial components of mRNA processing and autophagy-related pathways. ZFTRAF1 was completely absent in primary fibroblasts derived from two independent patients. Posthoc, profiling of autophagy markers, whole-transcriptome, and whole-proteome analyses discovered dysfunctional autophagy in patient-derived fibroblasts. The same, when attempted to be reprogrammed, could only achieve the pre-iPSCs phase, another indication of impaired autophagy. Briefly, discovered ZFTRAF1 as an indispensable novel component of neurodevelopment, and through multiple lines of evidence implicate its role in autophagy. Our findings suggest that biallelic variants of ZFTRAF1 cause severe neurodevelopmental disability syndrome and the loss-of-function leads to deficient autophagy and mRNA processing, both of which have crucial roles in normal human brain development.
HostingRepository	PRIDE
AnnounceDate	2024-10-17
AnnouncementXML	Submission_2024-10-17_03:11:53.884.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Anne Sanner
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	S-carboxamidoethyl-L-cysteine; monohydroxylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-08-22 05:32:31	ID requested
⏵ 1	2024-10-17 03:11:54	announced

Asif M, Khayyat AIA, Alawbathani S, Abdullah U, Sanner A, Georgomanolis T, Haasters J, Becker K, Budde B, Becker C, Thiele H, Baig SM, Isidoro-Garc, í, a M, Winter D, Pogoda HM, Muhammad S, Hammerschmidt M, Kraft F, Kurth I, Martin HG, Wagner M, N, ü, rnberg P, Hussain MS, Biallelic loss-of-function variants of ZFTRAF1 cause neurodevelopmental disorder with microcephaly and hypotonia. Genet Med, 26(7):101143(2024) [pubmed]

10.1016/j.gim.2024.101143;

submitter keyword: Microcephaly,Autophagy, ZFTRAF1

Muhammad Sajid Hussain
contact affiliation	Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne
contact email	mhussain@uni-koeln.de
lab head
Anne Sanner
contact affiliation	Institute for Biochemostry and Molecular Biology
contact email	anne.sanner@hotmail.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD044735
     1. Label: PRIDE project
     2. Name: Biallelic loss-of-function variants of ZFTRAF1 cause neurodevelopmental disorder with microcephaly and hypotonia by impairing autophagy