Defective Lamellar Granule Secretion in Arthrogryposis, Renal Dysfunction, and Cholestasis Syndrome Caused by a Mutation in VPS33B

Hershkovitz, Dov; Mandel, Hannah; Ishida‐Yamamoto, Akemi; Chefetz, Ilana; Bayan, Hino; Luder, Anthony; Indelman, Margarita; Bergman, Reuven; Sprecher, Eli

doi:10.1001/archderm.144.3.334

Cited by 49 publications

(52 citation statements)

References 20 publications

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“…Ultrastructural analysis by transmission electron microscopy revealed LB entombment and inclusion of lipid bilayers within corneocytes (Figure 5c and d), indicating entrapment of nonsecreted LB contents, inhomogeneous LB secretion (Figure 5e) with nonlamellar vesicular contents, and aberrant LB internal structures, suggesting defective loading into the organelles. This is similar to previous findings in ARC syndrome where abnormal LB-like structures within the stratum corneum were attributed to defects in LB secretion (Hershkovitz et al., 2008). …”

Section: Resultssupporting

confidence: 92%

“…The underlying pathology of the skin phenotype in VPS33B deficiency has previously been attributed to defective LB secretion (Hershkovitz et al., 2008), and Rab11a has recently been shown to be essential for LB biogenesis (Reynier et al., 2016). We demonstrate here that the p.Gly131Glu variant disrupts the interaction of VPS33B-VIPAR with Rab11a and VPS33B deficiency causes abnormal formation of LB structures in mouse and human epidermis, suggesting that this interaction with Rab11a is important for LB biogenesis.…”

Section: Discussionmentioning

confidence: 99%

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Autosomal Recessive Keratoderma-Ichthyosis-Deafness (ARKID) Syndrome Is Caused by VPS33B Mutations Affecting Rab Protein Interaction and Collagen Modification

Gruber

Rogerson

Windpassinger

et al. 2017

Journal of Investigative Dermatology

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In this paper, we report three patients with severe palmoplantar keratoderma associated with ichthyosis and sensorineural deafness. Biallelic mutations were found in VPS33B, encoding VPS33B, a Sec1/Munc18 family protein that interacts with Rab11a and Rab25 proteins and is involved in trafficking of the collagen-modifying enzyme LH3. Two patients were homozygous for the missense variant p.Gly131Glu, whereas one patient was compound heterozygous for p.Gly131Glu and the splice site mutation c.240-1G>C, previously reported in patients with arthrogryposis renal dysfunction and cholestasis syndrome. We demonstrated the pathogenicity of variant p.Gly131Glu by assessing the interactions of the mutant VPS33B construct and its ability to traffic LH3. Compared with wild-type VPS33B, the p.Gly131Glu mutant VPS33B had reduced coimmunoprecipitation and colocalization with Rab11a and Rab25 and did not rescue LH3 trafficking. Confirming the cell-based experiments, we found deficient LH3-specific collagen lysine modifications in patients’ urine and skin fibroblasts. Additionally, the epidermal ultrastructure of the p.Gly131Glu patients mirrored defects in tamoxifen-inducible VPS33B-deficient Vps33bfl/fl-ERT2 mice. Both patients and murine models revealed an impaired epidermal structure, ascribed to aberrant secretion of lamellar bodies, which are essential for epidermal barrier formation. Our results demonstrate that p.Gly131Glu mutant VPS33B causes an autosomal recessive keratoderma-ichthyosis-deafness syndrome.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Autosomal Recessive Keratoderma-Ichthyosis-Deafness (ARKID) Syndrome Is Caused by VPS33B Mutations Affecting Rab Protein Interaction and Collagen Modification

Gruber

Rogerson

Windpassinger

et al. 2017

Journal of Investigative Dermatology

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“…In ARC patients, the accumulation of lipofuscin has been previously reported in neonatal liver biopsies and granules containing lamellar and vesicular aggregates were detected in skin fibroblasts, whereas ultrastructural examination of the skin cornified cells revealed impaired secretion of lamellar granules. 34,35 The use of MKs cultured from BM-derived hematopoietic stem cells allowed the study of intermediate steps in a-granule biogenesis. Quantitative TEM analysis of BM-derived MKs in culture showed a reduction in a-granules and MVB II, and the presence of large vacuolar structures in Vps33b fl/fl -ER T2 mice.…”

mentioning

confidence: 99%

VPS33B regulates protein sorting into and maturation of α-granule progenitor organelles in mouse megakaryocytes

Bem

Smith

Banushi

et al. 2015

Blood

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Key Points• Hematologic effects in the mouse model for ARC syndrome, Vps33b fl/fl -ER T2, in which Vps33b is ubiquitously excised post-development.• The VPS33B-VIPAR complex is responsible for sorting cargo to and maturation of a-granule-destined MVBs.Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome is caused by deficiencies in the trafficking proteins VPS33B or VIPAR, and is associated with a bleeding diathesis and a marked reduction in platelet a-granules. We generated a tamoxifen-inducible mouse model of VPS33B deficiency, Vps33b

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“…Patients with ARC suffer severe ichthyosis. In this condition, LGs have abnormal morphology and exocytosis is defective [58,59].…”

Section: Doi: 101159/000491757mentioning

confidence: 99%

Epidermal Lamellar Granules

Wertz¹

2018

Skin Pharmacol Physiol

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In the mid-1950s and 1960s, transmission electron microscopes became widely available, leading to many studies of the ultrastructure of various tissues including the epidermis. Most of these studies involved tissue fixation with formaldehyde and postfixation with osmium tetroxide. A few studies employed freeze-fracture electron microscopy. One set of these studies identified a small organelle variously called lamellar granules (LGs), lamellar bodies, membrane-coating granules, cementsomes, and Odland bodies. LGs are round to ovoid in shape, with a diameter of about 200 nm. They have a bounding membrane surrounding a stack of internal lipid lamellae. These small organelles are first seen in the spinous layer and accumulate with differentiation in the granular layer. In the uppermost granular cells, the bounding membrane of the LG fuses into the cell plasma membrane, and the internal contents are extruded into the intercellular space. The initially extruded contents of the LG then rearrange to form the intercellular lamellae of the stratum corneum. In this context, LGs serve as the precursor to the permeability barrier of the skin. Various studies have provided evidence that they are derived from the Golgi apparatus, specifically the trans-Golgi. Isolated LGs contain phosphoglycerides, sphingomyelin, and glucosylceramides. The most unusual lipid component is a linoleate-containing glucosylceramide comprising 30- to 34-carbon ω-hydroxyacids. Isolated granules also contain acid hydrolases including glucocerebrosidase, sphingomyelinase, and phospholipase A. They also contain proteases and antimicrobial peptides. Defective LGs have been associated with a number of skin diseases including ichthyotic conditions and defective barrier function. Recently, studies employing cryo-transmission electron microscopy have called into question the validity of observations on LGs with more conventional electron microscopic techniques. These studies suggest a continuity of the membrane structure from the Golgi through the intercellular lamellae of the stratum corneum.

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Defective Lamellar Granule Secretion in Arthrogryposis, Renal Dysfunction, and Cholestasis Syndrome Caused by a Mutation in VPS33B

Cited by 49 publications

References 20 publications

Autosomal Recessive Keratoderma-Ichthyosis-Deafness (ARKID) Syndrome Is Caused by VPS33B Mutations Affecting Rab Protein Interaction and Collagen Modification

Autosomal Recessive Keratoderma-Ichthyosis-Deafness (ARKID) Syndrome Is Caused by VPS33B Mutations Affecting Rab Protein Interaction and Collagen Modification

VPS33B regulates protein sorting into and maturation of α-granule progenitor organelles in mouse megakaryocytes

Epidermal Lamellar Granules

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