Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease

Güngör, Serdal; Oktay, Yavuz; Hız, Semra; Aranguren-Ibáñez, Álvaro; Kalafatcilar, İpek Polat; Yaramış, Ahmet; Karaca, Ezgi; Yış, Uluç; Sonmezler, Ece; Ekinci, Burcu; Aslan, Mahmut; Yilmaz, Evrim; Özgör, Bilge; Sunitha, B.; Szabó, Nora; Laurie, Steven S.; Beltrán, Sergi; MacArthur, Daniel G.; Hathazi, Denisa; Töpf, Ana; Roos, Andreas; Lochmüller, Hanns; Vernos, Isabelle; Horvath, Rita

doi:10.1016/j.isci.2020.101948

Cited by 6 publications

(5 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To address the effect of arimoclomol on the fitness of VCP –mutant fibroblasts, an MTT–assay was carried out as described previously [ 22 ]. For that purpose, fibroblasts from two controls and three VCP –patients were analysed (eight replicates per sample) with and without supplementation of 10 µM arimoclomol (see above).…”

Section: Methodsmentioning

confidence: 99%

FYCO1 Increase and Effect of Arimoclomol–Treatment in Human VCP–Pathology

Güttsches

Meyer²,

Zahedi

et al. 2022

Biomedicines

View full text Add to dashboard Cite

Dominant VCP–mutations cause a variety of neurological manifestations including inclusion body myopathy with early–onset Paget disease and frontotemporal dementia 1 (IBMPFD). VCP encodes a ubiquitously expressed multifunctional protein that is a member of the AAA+ protein family, implicated in multiple cellular functions ranging from organelle biogenesis to ubiquitin–dependent protein degradation. The latter function accords with the presence of protein aggregates in muscle biopsy specimens derived from VCP–patients. Studying the proteomic signature of VCP–mutant fibroblasts, we identified a (pathophysiological) increase of FYCO1, a protein involved in autophagosome transport. We confirmed this finding applying immunostaining also in muscle biopsies derived from VCP–patients. Treatment of fibroblasts with arimoclomol, an orphan drug thought to restore physiologic cellular protein repair pathways, ameliorated cellular cytotoxicity in VCP–patient derived cells. This finding was accompanied by increased abundance of proteins involved in immune response with a direct impact on protein clearaqnce as well as by elevation of pro–survival proteins as unravelled by untargeted proteomic profiling. Hence, the combined results of our study reveal a dysregulation of FYCO1 in the context of VCP–etiopathology, highlight arimoclomol as a potential drug and introduce proteins targeted by the pre–clinical testing of this drug in fibroblasts.

show abstract

Section: Methodsmentioning

confidence: 99%

FYCO1 Increase and Effect of Arimoclomol–Treatment in Human VCP–Pathology

Güttsches

Meyer²,

Zahedi

et al. 2022

Biomedicines

View full text Add to dashboard Cite

show abstract

“…Over the past two decades, its methods have undergone significant expansion and improvement, allowing for the study of protein conformation, function, interactions, and posttranslational modification, among others [ 124 , 125 ]. In the field of ND research, proteomics has been employed in the quest for biomarker discovery (notably in autism) and in the study of the molecular mechanisms of disease [ 126 , 127 , 128 , 129 , 130 ]. In diagnostics, targeted proteomics can assist in assessing the consequences of the genetic variants discovered by NGS [ 131 ].…”

Section: Integrating Omics To Understand Functional Effects and Impro...mentioning

confidence: 99%

Methods to Improve Molecular Diagnosis in Genomic Cold Cases in Pediatric Neurology

Kadlubowska

Schrauwen

2022

Genes

View full text Add to dashboard Cite

During the last decade, genetic testing has emerged as an important etiological diagnostic tool for Mendelian diseases, including pediatric neurological conditions. A genetic diagnosis has a considerable impact on disease management and treatment; however, many cases remain undiagnosed after applying standard diagnostic sequencing techniques. This review discusses various methods to improve the molecular diagnostic rates in these genomic cold cases. We discuss extended analysis methods to consider, non-Mendelian inheritance models, mosaicism, dual/multiple diagnoses, periodic re-analysis, artificial intelligence tools, and deep phenotyping, in addition to integrating various omics methods to improve variant prioritization. Last, novel genomic technologies, including long-read sequencing, artificial long-read sequencing, and optical genome mapping are discussed. In conclusion, a more comprehensive molecular analysis and a timely re-analysis of unsolved cases are imperative to improve diagnostic rates. In addition, our current understanding of the human genome is still limited due to restrictions in technologies. Novel technologies are now available that improve upon some of these limitations and can capture all human genomic variation more accurately. Last, we recommend a more routine implementation of high molecular weight DNA extraction methods that is coherent with the ability to use and/or optimally benefit from these novel genomic methods.

show abstract

“…The identification of γTuRC populations with distinct, sub-centrosomal distribution and function warrants a more precise and differentiated terminology when referring to centrosomal γTuRC. Moreover, a more detailed analysis of γTuRC subpopulations is required in experiments where centrosomal γTuRC localization and activity are used as readouts, including the study of mutations in γTuRC subunits and regulators that have been linked to human disorders (Baldwin et al, 2021;Bond et al, 2005;Da Palma et al, 2020;Griffith et al, 2008;Gungor et al, 2021;Hassan et al, 2007;Hull et al, 2019;Issa et al, 2013;Martin et al, 2014;Maver et al, 2019;Mitani et al, 2019;Pagnamenta et al, 2012Pagnamenta et al, , 2016Puffenberger et al, 2012;Rafi and Butler, 2020;Scheidecker et al, 2015;Tan et al, 2014). In the absence of such analysis, the findings have to be interpreted with caution.…”

Section: Conclusion and Future Challengesmentioning

confidence: 99%

From tip to toe – dressing centrioles in γTuRC

Schweizer

Lüders

2021

Journal of Cell Science

View full text Add to dashboard Cite

Centrioles are microtubule-based cylindrical structures that assemble the centrosome and template the formation of cilia. The proximal part of centrioles is associated with the pericentriolar material, a protein scaffold from which microtubules are nucleated. This activity is mediated by the γ-tubulin ring complex (γTuRC) whose central role in centrosomal microtubule organization has been recognized for decades. However, accumulating evidence suggests that γTuRC activity at this organelle is neither restricted to the pericentriolar material nor limited to microtubule nucleation. Instead, γTuRC is found along the entire centriole cylinder, at subdistal appendages, and inside the centriole lumen, where its canonical function as a microtubule nucleator might be supplemented or replaced by a function in microtubule anchoring and centriole stabilization, respectively. In this Opinion, we discuss recent insights into the expanded repertoire of γTuRC activities at centrioles and how distinct subpopulations of γTuRC might act in concert to ensure centrosome and cilia biogenesis and function, ultimately supporting cell proliferation, differentiation and homeostasis. We propose that the classical view of centrosomal γTuRC as a pericentriolar material-associated microtubule nucleator needs to be revised.

show abstract

Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease

Cited by 6 publications

References 50 publications

FYCO1 Increase and Effect of Arimoclomol–Treatment in Human VCP–Pathology

FYCO1 Increase and Effect of Arimoclomol–Treatment in Human VCP–Pathology

Methods to Improve Molecular Diagnosis in Genomic Cold Cases in Pediatric Neurology

From tip to toe – dressing centrioles in γTuRC

Contact Info

Product

Resources

About