Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking

Sanderson, Leslie E.; Lanko, Kristina; Alsagob, Maysoon; Almass, Rawan; Al-Ahmadi, Nada; Najafi, Maryam; Al–Muhaizea, Mohammad A.; Alzaidan, Hamad; Aldhalaan, Hesham; Perenthaler, Elena; Linde, Herma C. van der; Nikoncuk, Anita; Kühn, Nikolas A; Antony, Dinu; Owaidah, Tarek Mustafa; Raskin, Salmo; Vieira, Luana Gabriela Dalla Rosa; Mombach, Romulo; Ahangari, Najmeh; Silveira, Tainá Regina Damaceno; Ameziane, Najim; Rolfs, Arndt; Alharbi, Aljohara; Sabbagh, Raghda M; AlAhmadi, Khalid; Alawam, Bashayer S; Ghebeh, Hazem; AlHargan, Aljouhra; Albader, Anoud; BinHumaid, Faisal S.; Goljan, Ewa; Monies, Dorota; Mustafa, Osama M.; Aldosary, Mazhor; Al-Bakheet, Albandary; Al-Younes, Banan; Almutairi, Faten; Al‐Odaib, Ali; Aksoy, Dürdane; Başak, A. Nazlı; Palvadeau, Robin; Trabzuni, Daniah; Rosenfeld, Jill A.; Karimiani, Ehsan Ghayoor; Meyer, Brian F.; Karakas, Bedri; Al‐Mohanna, Futwan; Arold, Stefan T.; Çolak, Dilek; Maroofian, Reza; Houlden, Henry; Bertoli‐Avella, Aida M.; Schmidts, Miriam; Barakat, Tahsin Stefan; Ham, Tjakko J. van; Kaya, Namik

doi:10.1093/brain/awaa459

Cited by 38 publications

(32 citation statements)

References 37 publications

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“…For in vitro experiments flag-tagged wild type (kindly provided by David Skalnik, Indiana University [5]) and variant SETD1B protein and HA-tagged ASH2 were overexpressed in HEK293 cells. Protein expression, isolation, western blotting, and immunocytochemistry were performed following standard procedures [26][27][28]. Genome-wide methylation profiles were obtained as described [8].…”

Section: Methodsmentioning

confidence: 99%

Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

Weerts

Lanko

Guzmán‐Vega

et al. 2021

Genetics in Medicine

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Purpose Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. Methods We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Results Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Conclusion Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

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Section: Methodsmentioning

confidence: 99%

Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

Weerts

Lanko

Guzmán‐Vega

et al. 2021

Genetics in Medicine

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“…Although these diseases likely also have major non-microglial components, the effects seen in microglia appear to be cell-autonomous and not simply responses to pathological processes in other cells of the CNS. This is reminiscent of lysosomal storage disorder phenotypes in zebrafish models (Box 2: The Zebrafish -In Vivo Modelling of Glial Cell Dynamics and Myelination in Genetic Brain Disorders), in which abnormal microglia are typically seen in very early embryogenesis, right at the stages at which they seem to shape brain development (Berg et al, 2016;Kuil et al, 2019a;Sanderson et al, 2021).…”

Section: Primary Lysosome or Peroxisome Dysfunction In Leukodystrophies: Making A Case For Microgliamentioning

confidence: 99%

The multicellular interplay of microglia in health and disease: lessons from leukodystrophy

Berdowski

Sanderson

Ham

2021

Disease Models &Amp; Mechanisms

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Microglia are highly dynamic cells crucial for developing and maintaining lifelong brain function and health through their many interactions with essentially all cellular components of the central nervous system. The frequent connection of microglia to leukodystrophies, genetic disorders of the white matter, has highlighted their involvement in the maintenance of white matter integrity. However, the mechanisms that underlie their putative roles in these processes remain largely uncharacterized. Microglia have also been gaining attention as possible therapeutic targets for many neurological conditions, increasing the demand to understand their broad spectrum of functions and the impact of their dysregulation. In this Review, we compare the pathological features of two groups of genetic leukodystrophies: those in which microglial dysfunction holds a central role, termed ‘microgliopathies’, and those in which lysosomal or peroxisomal defects are considered to be the primary driver. The latter are suspected to have notable microglia involvement, as some affected individuals benefit from microglia-replenishing therapy. Based on overlapping pathology, we discuss multiple ways through which aberrant microglia could lead to white matter defects and brain dysfunction. We propose that the study of leukodystrophies, and their extensively multicellular pathology, will benefit from complementing analyses of human patient material with the examination of cellular dynamics in vivo using animal models, such as zebrafish. Together, this will yield important insight into the cell biological mechanisms of microglial impact in the central nervous system, particularly in the development and maintenance of myelin, that will facilitate the development of new, and refinement of existing, therapeutic options for a range of brain diseases.

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“…The lossof-function of the PARLA gene decreases dopaminergic neurons mainly in the olfactory bulb (Merhi et al, 2021). VPS41 knockout causes lysosomal abnormalities as well as microglial and cerebellar dysfunction (Sanderson et al, 2021). NUS1 knockdown zebrafish exhibit movement deficits caused by defective efflux of cholesterol from lysosomes (Yu et al, 2021).…”

Section: Genetic Zebrafish Models Of Parkinson's Diseasementioning

confidence: 99%

Advances of Zebrafish in Neurodegenerative Disease: From Models to Drug Discovery

Wang

Zhang

et al. 2021

Front. Pharmacol.

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Neurodegenerative disease (NDD), including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, are characterized by the progressive loss of neurons which leads to the decline of motor and/or cognitive function. Currently, the prevalence of NDD is rapidly increasing in the aging population. However, valid drugs or treatment for NDD are still lacking. The clinical heterogeneity and complex pathogenesis of NDD pose a great challenge for the development of disease-modifying therapies. Numerous animal models have been generated to mimic the pathological conditions of these diseases for drug discovery. Among them, zebrafish (Danio rerio) models are progressively emerging and becoming a powerful tool for in vivo study of NDD. Extensive use of zebrafish in pharmacology research or drug screening is due to the high conserved evolution and 87% homology to humans. In this review, we summarize the zebrafish models used in NDD studies, and highlight the recent findings on pharmacological targets for NDD treatment. As high-throughput platforms in zebrafish research have rapidly developed in recent years, we also discuss the application prospects of these new technologies in future NDD research.

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Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking

Cited by 38 publications

References 37 publications

Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

The multicellular interplay of microglia in health and disease: lessons from leukodystrophy

Advances of Zebrafish in Neurodegenerative Disease: From Models to Drug Discovery

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