Dataset Information

Biallelic loss-of-function variants of ZFTRAF1 cause neurodevelopmental disorder with microcephaly and hypotonia by impairing autophagy

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Anne Sanner

LAB HEAD: Muhammad Sajid Hussain

PROVIDER: PXD044735 | Pride | 2024-10-17

REPOSITORIES: Pride

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			Action	DRS
	20211122_AS_Cologne_DDA_CUHR1-SPN_pooled.raw	Raw
	20211122_AS_Cologne_DDA_WT_pooled.raw	Raw
	20211122_AS_Cologne_DIA_CUHR1-SPN_R1.raw	Raw
	20211122_AS_Cologne_DIA_CUHR1-SPN_R2.raw	Raw
	20211122_AS_Cologne_DIA_CUHR1-SPN_R3.raw	Raw

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

Asif Maria M Khayyat Arwa Ishaq A AIA Alawbathani Salem S Abdullah Uzma U Sanner Anne A Georgomanolis Theodoros T Haasters Judith J Becker Kerstin K Budde Birgit B Becker Christian C Thiele Holger H Baig Shahid M SM Isidoro-García María M Winter Dominic D Pogoda Hans-Martin HM Muhammad Sajjad S Hammerschmidt Matthias M Kraft Florian F Kurth Ingo I Martin Hilario Gomez HG Wagner Matias M Nürnberg Peter P Hussain Muhammad Sajid MS

Genetics in medicine : official journal of the American College of Medical Genetics 20240416 7

<h4>Purpose</h4>Neurodevelopmental disorders exhibit clinical and genetic heterogeneity, ergo manifest dysfunction in components of diverse cellular pathways; the precise pathomechanism for the majority remains elusive.<h4>Methods</h4>We studied 5 affected individuals from 3 unrelated families manifesting global developmental delay, postnatal microcephaly, and hypotonia. We used exome sequencing and prioritized variants that were subsequently characterized using immunofluorescence, immunoblottin ...[more]

PMID: 38641995

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