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XK is a partner for VPS13A: a molecular link between Chorea-Acanthocytosis and McLeod Syndrome.

ABSTRACT: Vps13 is a highly conserved lipid transfer protein found at multiple interorganelle membrane contact sites where it mediates distinct processes. In yeast, recruitment of Vps13 to different contact sites occurs via various partner proteins. In humans, four VPS13 family members, A-D, are associated with different diseases. In particular, vps13A mutants result in the neurodegenerative disorder Chorea-Acanthocytosis (ChAc). ChAc phenotypes resemble those of McLeod Syndrome, caused by mutations in the XK gene, suggesting that XK could be a partner protein for VPS13A. XK does, in fact, exhibit hallmarks of a VPS13A partner: it forms a complex with VPS13A in human cells and, when overexpressed, relocalizes VPS13A from lipid droplets to subdomains of the endoplasmic reticulum. Introduction of two different ChAc disease-linked missense mutations into VPS13A prevents this XK-induced relocalization. These results suggest that dysregulation of a VPS13A-XK complex is the common basis for ChAc and McLeod Syndrome.

SUBMITTER: Park JS

PROVIDER: S-EPMC7851852 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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XK is a partner for VPS13A: a molecular link between Chorea-Acanthocytosis and McLeod Syndrome.

Park Jae-Sook JS Neiman Aaron M AM

Molecular biology of the cell 20200826 22

Vps13 is a highly conserved lipid transfer protein found at multiple interorganelle membrane contact sites where it mediates distinct processes. In yeast, recruitment of Vps13 to different contact sites occurs via various partner proteins. In humans, four VPS13 family members, A-D, are associated with different diseases. In particular, <i>vps13A</i> mutants result in the neurodegenerative disorder Chorea-Acanthocytosis (ChAc). ChAc phenotypes resemble those of McLeod Syndrome, caused by mutation ...[more]

PMID: 32845802

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Project description:BackgroundMcLeod syndrome (MLS) is an X-linked multisystemic progressive disorder caused by loss of function mutations in the XK gene. The rare blood group phenotype of MLS patients with absent Kx antigen requires the support of specialized transfusion institutions because of the risk of transfusion complications. Acanthocytosis of red blood cells occurs in almost all patients. Nonhematological manifestations of MLS are very similar to those of VPS13A disease (chorea-acanthocytosis), an autosomal-recessive condition. Their shared phenotype apart from acanthocytosis includes movement disorders such as chorea and dystonia, epilepsy, peripheral neuropathy, and muscle involvement, typically with creatine kinase (CK) elevation, cardiomyopathy included.SummaryIn this review, we describe the nonhematological manifestations of MLS in comparison with those of VPS13A disease. While there are many similarities, differences such as mode of inheritance, sex distribution, age at manifestation, severity of heart involvement, frequency of feeding dystonia or of involuntary head drops may help to distinguish these disorders in the clinic. Immunohematological demonstration of the McLeod-Kell phenotype or detection of pathogenic mutations of XK (or VPS13A, respectively) is the gold standard for distinction. "Neuroacanthocytosis" was often used as an overarching term, but is potentially misleading, as the term does not refer to a defined disease entity. Its use, if continued, must not prevent clinicians to seek a final diagnosis on the basis of molecular findings. The clinical similarity of MLS and VPS13A disease has long suggested some shared pathophysiology. Evidence for molecular interaction between XK, the McLeod protein, and chorein, the VPS13A gene product, has recently been put forward: XK forms a complex with chorein/VPS13A, a bulk lipid transporter located at various membrane contact sites. The exact role of XK in this complex needs to be further elucidated. Impairment of bulk lipid transport appears as the common denominator of both MLS and VPS13A disease. A variety of further conditions may in time be added to the "bulk lipid transport diseases," such as the recently recognized disorders caused by mutations in the VPS13B, VPS13C, and VPS13D genes.Key messages(1) Patients diagnosed with the rare red cell McLeod phenotype (McLeod syndrome, MLS) require interdisciplinary collaboration of transfusion medicine specialists, neurologists, and cardiologists for both their hematological and nonhematological disease manifestations. (2) The phenotypical similarity of MLS and VPS13A disease, often leading to either confusion or insufficient diagnostic depth (under the label of "neuroacanthocytosis"), is based on interaction of the respective proteins, XK and chorein, within the cellular machinery for bulk lipid transport. (3) Overall, the term "bulk lipid transport diseases" seems useful for further research on a group of conditions that may not only share pathophysiology, but may also share treatment approaches.

Dataset Information

XK is a partner for VPS13A: a molecular link between Chorea-Acanthocytosis and McLeod Syndrome.

Publications

XK is a partner for VPS13A: a molecular link between Chorea-Acanthocytosis and McLeod Syndrome.

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