<i>VPS26C</i> homozygous nonsense variant in two cousins with neurodevelopmental deficits, growth failure, skeletal abnormalities, and distinctive facial features

Beetz, Christian; Ameziane, Najim; Kdissa, Ameni; Karageorgou, Vasiliki; Bauer, Péter; Suleiman, Jehan; Sutton, V. Reid; El‐Hattab, Ayman W.

doi:10.1111/cge.13690

Cited by 3 publications

(3 citation statements)

References 14 publications

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“…Furthermore, a homozygous nonsense variant in VPS26C was described in individuals with a pleiotropic syndrome characterized by neurodevelopmental defects, growth failure, skeletal anomalies, and distinctive facial features. 59 Previous studies have already reported mutations in subunits of the CCC and WASH complexes that cause neurodevelopmental disorders. For example, mutations in WASHC4 and WASHC5 have been identified in patients with non-syndromic autosomal recessive intellectual disability 60 and 3C/RSS, 61 respectively, and mutations in CCDC22 cause X-linked recessive intellectual disability (XLID) with clinical features of 3C/RSS.…”

Section: Discussionmentioning

confidence: 99%

Cargo-Specific Role for Retriever Subunit VPS26C in Hepatocyte Lipoprotein Receptor Recycling to Control Postprandial Triglyceride-Rich Lipoproteins

Vos

Wijers

Smit

et al. 2023

ATVB

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BACKGROUND: The coiled-coil domain containing 22/coiled-coil domain containing 93/copper metabolism MURR1 domains (CCC) complex is required for the transport of low-density lipoprotein receptor (LDLR) and LRP1 (LDLR-related protein 1) from endosomes to the cell surface of hepatocytes. Impaired functioning of hepatocytic CCC causes hypercholesterolemia in mice, dogs, and humans. Retriever, a protein complex consisting of subunits VPS26C, VPS35L, and VPS29, is associated with CCC, but its role in endosomal lipoprotein receptor transport is unclear. We here investigated the contribution of retriever to hepatocytic lipoprotein receptor recycling and plasma lipids regulation. METHODS: Using somatic CRISPR/Cas9 gene editing, we generated liver-specific VPS35L or VPS26C-deficient mice. We determined total and surface levels of LDLR and LRP1 and plasma lipids. In addition, we studied the protein levels and composition of CCC and retriever. RESULTS: Hepatocyte VPS35L deficiency reduced VPS26C levels but had minimal impact on CCC composition. VPS35L deletion decreased hepatocytic surface expression of LDLR and LRP1, accompanied by a 21% increase in plasma cholesterol levels. Hepatic VPS26C ablation affected neither levels of VPS35L and CCC subunits, nor plasma lipid concentrations. However, VPS26C deficiency increased hepatic LDLR protein levels by 2-fold, probably compensating for reduced LRP1 functioning, as we showed in VPS26C-deficient hepatoma cells. Upon PCSK9 (proprotein convertase subtilisin/kexin type 9)-mediated LDLR elimination, VPS26C ablation delayed postprandial triglyceride clearance and increased plasma TG levels by 26%. CONCLUSIONS: Our study suggests that VPS35L is shared between retriever and CCC to facilitate LDLR and LRP1 transport from endosomes to the cell surface. Conversely, retriever subunit VPS26C selectively transports LRP1, but not LDLR, and thereby may control hepatic uptake of postprandial TG-rich lipoprotein remnants.

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Section: Discussionmentioning

confidence: 99%

Cargo-Specific Role for Retriever Subunit VPS26C in Hepatocyte Lipoprotein Receptor Recycling to Control Postprandial Triglyceride-Rich Lipoproteins

Vos

Wijers

Smit

et al. 2023

ATVB

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“…In addition to the clinical utility, exome sequencing has been an essential tool in the discovery of novel genes associated with neurodevelopmental disorders 3 . While sequencing studies in outbred populations have revealed many dominant disease‐causing genes, studies in consanguineous families have aided in the discovery of recessive disease‐causing genes 4,5 . Herein we present four children from three related families with a unique syndromic phenotype and a homozygous frame‐shift variant in PROSER1 .…”

Section: Introductionmentioning

confidence: 99%

“…3 While sequencing studies in outbred populations have revealed many dominant disease-causing genes, studies in consanguineous families have aided in the discovery of recessive disease-causing genes. 4,5 Herein we present four children from three related families with a unique syndromic phenotype and a homozygous frame-shift variant in PROSER1.…”

Section: Introductionmentioning

confidence: 99%

A homozygous frame‐shift variant in PROSER1 is associated with developmental delay, hypotonia, genitourinary malformations, and distinctive facial features

Salah

Almannai²,

Ojaimi

et al. 2022

Clinical Genetics

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We report four children from three related families who presented with a similar phenotype characterized by developmental delay, hypotonia, seizures, failure‐to‐thrive, strabismus, drooling, recurrent otitis media, hearing impairment, and genitourinary malformations. They also shared common facial features including arched eyebrows, prominent eyes, broad nasal bridge, low‐hanging columella, open mouth, thick lower lip, protruding tongue, large low‐set ears, and parietal bossing. Exome sequencing for affected individuals revealed a homozygous frame‐shift variant, c.1833del; p.(Thr612Glnfs*22), in PROSER1 which encodes the proline and serine rich protein 1 (PROSER1). PROSER1 has recently been found to be part of the histone methyltransferases KMT2C/KMT2D complexes. PROSER1 stabilizes TET2, a member of the TET family of DNA demethylases which is involved in recruiting the enhancer‐associated KMT2C/KMT2D complexes and mediating DNA demethylation, activating gene expression. Therefore, PROSER1 may play vital and potentially general roles in gene regulation, consistent with the wide phenotypic spectrum observed in the individuals presented here. The consistent phenotype, the loss‐of‐function predicted from the frame‐shift, the co‐segregation of the phenotype in our large pedigree, the vital role of PROSER1 in gene regulation, and the association of related genes with neurodevelopmental disorders argue for the loss of PROSER1 to be the cause for a novel recognizable syndrome.

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Explosion in the complexity of membrane protein recycling

McDonald

2021

American Journal of Physiology-Cell Physiology

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For decades, recycling of membrane proteins has been represented in figures by arrows between the 'endosome' and the plasma membrane, but recently there has been an explosion in the understanding of the mechanisms and protein complexes required to facilitate protein recycling. Here, some key discoveries will be introduced, including assigning function to a number of recently recognized protein complexes, and linking their function to protein recycling. Further, the importance of lipid interactions, and links to diseases and epithelial polarity will be summarized.

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VPS26C homozygous nonsense variant in two cousins with neurodevelopmental deficits, growth failure, skeletal abnormalities, and distinctive facial features

Cited by 3 publications

References 14 publications

Cargo-Specific Role for Retriever Subunit VPS26C in Hepatocyte Lipoprotein Receptor Recycling to Control Postprandial Triglyceride-Rich Lipoproteins

Cargo-Specific Role for Retriever Subunit VPS26C in Hepatocyte Lipoprotein Receptor Recycling to Control Postprandial Triglyceride-Rich Lipoproteins

A homozygous frame‐shift variant in PROSER1 is associated with developmental delay, hypotonia, genitourinary malformations, and distinctive facial features

Explosion in the complexity of membrane protein recycling

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