VPS13B — Vacuolar protein sorting 13 homolog B

The VPS13B gene acts like an instruction manual for making a protein that works in a part of the cell called the Golgi apparatus. Think of the Golgi as the cell's shipping and receiving center, where proteins and fats are modified, packaged, and sent to their correct destinations. The VPS13B protein helps keep this shipping center organized and functioning properly, particularly by moving fats between different parts of the cell. It plays an important role in the healthy growth and development of nerve cells in the brain and cells that store fat. When a person inherits two mutated copies of the VPS13B gene, their cells cannot produce a working version of this protein. Without it, the cell's shipping center becomes disorganized and fragmented, leading to a condition called Cohen syndrome. Because the brain and eyes rely heavily on the proper functioning of these cellular processes, people with Cohen syndrome often experience developmental delays, intellectual disability, and progressive vision loss (retinal dystrophy). The disruption in fat storage cells also contributes to the characteristic weight gain around the torso (truncal obesity) seen in this condition.

Gene description: The VPS13B gene provides instructions for making a protein that is part of the Golgi apparatus, where it is involved in protein modification (glycosylation) and the sorting and transporting of proteins and lipids. Mutations in this gene cause Cohen syndrome, a disorder characterized by intellectual disability, distinctive facial features, truncal obesity, and vision problems.

Patient and family guide: The VPS13B gene acts like an instruction manual for making a protein that works in a part of the cell called the Golgi apparatus. Think of the Golgi as the cell's shipping and receiving center, where proteins and fats are modified, packaged, and sent to their correct destinations. The VPS13B protein helps keep this shipping center organized and functioning properly, particularly by moving fats between different parts of the cell. It plays an important role in the healthy growth and development of nerve cells in the brain and cells that store fat. When a person inherits two mutated copies of the VPS13B gene, their cells cannot produce a working version of this protein. Without it, the cell's shipping center becomes disorganized and fragmented, leading to a condition called Cohen syndrome. Because the brain and eyes rely heavily on the proper functioning of these cellular processes, people with Cohen syndrome often experience developmental delays, intellectual disability, and progressive vision loss (retinal dystrophy). The disruption in fat storage cells also contributes to the characteristic weight gain around the torso (truncal obesity) seen in this condition.

Gene function: The VPS13B protein is a bridge-like lipid transfer protein (BLTP) that localizes primarily to the Golgi apparatus. It mediates the transfer of lipids between membranes at organelle contact sites, potentially forming connections between different Golgi cisternae. It is essential for maintaining Golgi architecture and function, including normal glycosylation and intracellular protein sorting and transport.

Protein structure: VPS13B is a large protein (~450 kDa) characterized by a central rod-like structure formed by repeated beta-groove (RBG) units that create a hydrophobic tunnel for lipid transport. It contains four folded accessory domains in its C-terminal region: a Vps13 adaptor binding (VAB) domain, an ATC2-C (Gondola) domain, a pleckstrin homology (PH) domain, and a unique jellyroll/beta-sandwich domain.

Molecular function: VPS13B functions as a lipid transfer protein that facilitates bulk lipid flow between adjacent organelle membranes, particularly within the Golgi complex. It contains a hydrophobic tunnel formed by repeated beta-groove (RBG) units that allows for lipid transport. The protein interacts with various partners, including the small GTPase RAB6 and SNARE proteins like Syntaxin 6 and 13, to regulate Golgi dynamics, vesicle-mediated sorting, and intracellular trafficking. It also binds phosphatidylinositol 3-phosphate and plays a role in maintaining Golgi integrity and supporting normal cellular processes such as neuron development and adipogenesis.

Mutation spectrum: Over 660 pathogenic variants have been identified in the VPS13B gene, the vast majority being truncating loss-of-function mutations such as nonsense, frameshift, splice site mutations, and large exon-spanning deletions or insertions. A smaller number of missense variants have also been reported. A common 2-bp deletion (c.3348_3349delCT) is prevalent in the Finnish population, while specific insertion and missense mutations are found in the Amish population.

Clinical significance: Mutations in the VPS13B gene lead to Cohen syndrome, an autosomal recessive neurodevelopmental disorder. Loss of functional VPS13B protein disrupts the organization of the Golgi apparatus, leading to Golgi fragmentation and impaired normal glycosylation. This cellular dysfunction is thought to underlie the clinical features of Cohen syndrome, including intellectual disability, developmental delay, microcephaly, distinctive facial features, truncal obesity, neutropenia, and progressive retinal dystrophy. The exact mechanisms linking Golgi impairment to these specific symptoms remain under investigation, but defective neuron development and abnormal fat storage are likely key factors.

Inheritance: Autosomal Recessive

Chromosomal location: 8q22.2

Research and therapeutic approaches: Currently, there are no specific gene therapies or targeted treatments for Cohen syndrome; management is primarily symptomatic. However, preclinical research is exploring drug repurposing of FDA-approved small pharmaceutical compounds that have shown the ability to revert the impaired Golgi morphology in VPS13B-deficient cells. These candidates are being assessed in mouse models for their potential to treat the underlying cellular defects.