Novel VPS33B mutation in a patient with autosomal recessive keratoderma‐ichthyosis‐deafness syndrome

Alter, Svenja; Hotz, Alrun; Jahn, Arne; Donato, Nataliya Di; Smitka, Martin; Hagen, Maja von der; Schallner, Jens; Menschikowski, Mario; Gillitzer, Claus; Laaß, Martin W.; Fischer, Judith; Tzschach, Andreas

doi:10.1002/ajmg.a.40634

Cited by 9 publications

(9 citation statements)

References 15 publications

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“…The prevalence of ARC syndrome has not been accurately described, but estimates from gnomAD using the Hardy‐Weinberg principle indicate a carrier frequency of loss‐of‐function variants in VPS33B and VIPAS39 of approximately 9.12e‐6. The broad spectrum of clinical presentations provides additional challenges, as demonstrated by the recent association of autosomal recessive keratoderma‐ichthyosis‐deafness syndrome with biallelic variants in VPS33B in patients in which ARC syndrome was not clinically suspected 29,30 . Further systematic examination of VPS33B and VPS16B expression levels and interactions in primary cells from patients with variants associated with a range of clinical presentations would increase understanding of the roles of these proteins in α‐granule biogenesis and other cellular functions.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, autosomal recessive keratoderma-ichthyosis-deafness syndrome has recently been associated with rare biallelic variants in VPS33B and may represent a mild phenotypic variant of ARC syndrome rather than a distinct disorder. 29,30 It is not surprising that in diseases involving genes that encode components of multimeric protein complexes, loss of one protein can destabilize the entire complex, as seen, for example, in Hermansky-Pudlak syndrome. 22,23 In vitro studies have indicated that VPS33B and VPS16B (VIPAS39) form a protein complex, 14,15 and knockout of VPS33B in a human megakaryocytic cell line causes severe depletion of VPS16B.…”

Section: Essentialsmentioning

confidence: 99%

“…[36][37][38] The prevalence of ARC syndrome has not been accurately described, but estimates from syndrome with biallelic variants in VPS33B in patients in which ARC syndrome was not clinically suspected. 29,30 Further systematic examination of VPS33B and VPS16B expression levels and interactions in primary cells from patients with variants associated with a range of clinical presentations would increase understanding of the roles of these proteins in α-granule biogenesis and other cellular functions.…”

Section: Expression Of Vps33b and Vps16b In Plateletsmentioning

confidence: 99%

“…However, only VPS33B variants have been clearly described in association with a milder form of ARC syndrome and prolonged survival. Furthermore, autosomal recessive keratoderma‐ichthyosis‐deafness syndrome has recently been associated with rare biallelic variants in VPS33B and may represent a mild phenotypic variant of ARC syndrome rather than a distinct disorder 29,30 …”

Section: Introductionmentioning

confidence: 99%

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Platelet VPS16B is dependent on VPS33B expression, as determined in two siblings with arthrogryposis, renal dysfunction, and cholestasis syndrome

Penón-Portmann

Westbury

et al. 2022

Journal of Thrombosis and Haemostasis

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Background Platelet α‐granule biogenesis in precursor megakaryocytes is critically dependent on VPS33B and VPS16B, as demonstrated by the platelet α‐granule deficiency seen in the rare multisystem disorder arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome associated with biallelic pathogenic variants in VPS33B and VIPAS39 (encoding VPS16B). VPS33B and VPS16B are ubiquitously expressed proteins that are known to interact and play key roles in protein sorting and trafficking between subcellular locations. However, there remain significant gaps in our knowledge of the nature of these interactions in primary cells from patients with ARC syndrome. Objectives To use primary cells from patients with ARC syndrome to better understand the interactions and roles of VPS33B and VPS16B in platelets and precursor megakaryocytes. Patients/methods The proband and his male sibling were clinically suspected to have ARC syndrome. Confirmatory genetic testing and platelet phenotyping, including electron microscopy and protein expression analysis, was performed with consent in a research setting. Results We describe the first case of ARC syndrome identified in Costa Rica, associated with a novel homozygous nonsense VPS33B variant that is linked with loss of expression of both VPS33B and VPS16B in platelets. Conclusion These results indicate that stable expression of VPS16B in platelets, their precursor megakaryocytes, and other cells is dependent on VPS33B. We suggest that systematic evaluation of primary cells from patients with a range of VPS33B and VIPAS39 variants would help to elucidate the interactions and functions of these proteins.

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Section: Resultsmentioning

confidence: 99%

Section: Essentialsmentioning

confidence: 99%

Section: Expression Of Vps33b and Vps16b In Plateletsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Platelet VPS16B is dependent on VPS33B expression, as determined in two siblings with arthrogryposis, renal dysfunction, and cholestasis syndrome

Penón-Portmann

Westbury

et al. 2022

Journal of Thrombosis and Haemostasis

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“…The main symptoms are arthrogryposis multiplex congenita (congenital joint contraction), renal tubular dysfunction and cholestasis (inability of bile to flow from the liver to the duodenum). Additional features include platelet anomalies, central nervous system malformation and ichthyosis (a skin disorder) (Abu-Sa' Da et al, 2005;Alter et al, 2018;Hershkovitz et al, 2008). The symptoms of ARC patients can be largely explained by the major roles of CHEVI in protein recycling and LRO biogenesis (Cullinane et al, 2010;Rogerson and Gissen, 2016).…”

Section: Arc Syndromementioning

confidence: 99%

CORVET, CHEVI and HOPS – multisubunit tethers of the endo-lysosomal system in health and disease

Beek

Jonker

Welle

et al. 2019

Journal of Cell Science

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Multisubunit tethering complexes (MTCs) are multitasking hubs that form a link between membrane fusion, organelle motility and signaling. CORVET, CHEVI and HOPS are MTCs of the endo-lysosomal system. They regulate the major membrane flows required for endocytosis, lysosome biogenesis, autophagy and phagocytosis. In addition, individual subunits control complex-independent transport of specific cargoes and exert functions beyond tethering, such as attachment to microtubules and SNARE activation. Mutations in CHEVI subunits lead to arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome, while defects in CORVET and, particularly, HOPS are associated with neurodegeneration, pigmentation disorders, liver malfunction and various forms of cancer. Diseases and phenotypes, however, vary per affected subunit and a concise overview of MTC protein function and associated human pathologies is currently lacking. Here, we provide an integrated overview on the cellular functions and pathological defects associated with CORVET, CHEVI or HOPS proteins, both with regard to their complexes and as individual subunits. The combination of these data provides novel insights into how mutations in endo-lysosomal proteins lead to human pathologies.

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An update on autophagy disorders

Dafsari,

Martinelli,

Saffari

et al. 2024

J of Inher Metab Disea

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Macroautophagy is a highly conserved cellular pathway for the degradation and recycling of defective cargo including proteins, organelles, and macromolecular complexes. As autophagy is particularly relevant for cellular homeostasis in post‐mitotic tissues, congenital disorders of autophagy, due to monogenic defects in key autophagy genes, share a common “clinical signature” including neurodevelopmental, neurodegenerative, and neuromuscular features, as well as variable abnormalities of the eyes, skin, heart, bones, immune cells, and other organ systems, depending on the expression pattern and the specific function of the defective proteins. Since the clinical and genetic resolution of EPG5‐related Vici syndrome, the paradigmatic congenital disorder of autophagy, the widespread use of massively parallel sequencing has resulted in the identification of a growing number of autophagy‐associated disease genes, encoding members of the core autophagy machinery as well as related proteins. Recently identified monogenic disorders linking selective autophagy, vesicular trafficking, and other pathways have further expanded the molecular and phenotypical spectrum of congenital disorders of autophagy as a clinical disease spectrum. Moreover, significant advances in basic research have enhanced the understanding of the underlying pathophysiology as a basis for therapy development. Here, we review (i) autophagy in the context of other intracellular trafficking pathways; (ii) the main congenital disorders of autophagy and their typical clinico‐pathological signatures; and (iii) the recommended primary health surveillance in monogenic disorders of autophagy based on available evidence. We further discuss recently identified molecular mechanisms that inform the current understanding of autophagy in health and disease, as well as perspectives on future therapeutic approaches.

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Novel VPS33B mutation in a patient with autosomal recessive keratoderma‐ichthyosis‐deafness syndrome

Cited by 9 publications

References 15 publications

Platelet VPS16B is dependent on VPS33B expression, as determined in two siblings with arthrogryposis, renal dysfunction, and cholestasis syndrome

Platelet VPS16B is dependent on VPS33B expression, as determined in two siblings with arthrogryposis, renal dysfunction, and cholestasis syndrome

CORVET, CHEVI and HOPS – multisubunit tethers of the endo-lysosomal system in health and disease

An update on autophagy disorders

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