A novel missense mutation in <i>SCYL1BP1</i> produces geroderma osteodysplastica phenotype indistinguishable from that caused by nullimorphic mutations

Al‐Dosari, Mohammed S.; Alkuraya, Fowzan S.

doi:10.1002/ajmg.a.32996

Cited by 31 publications

(24 citation statements)

References 17 publications

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“…Recent evidence demonstrates that Scyl1BP1 (also known as Golgi-associated Rab-binding protein or GORAB) binds Rab6 in a GTP-dependant manner and localizes to the Golgi, prompting the authors to classify GORAB as a golgin [31]. Interestingly, when mutated, GORAB results in Gerodermia Osteodysplastica (GO) in humans [31], [32]. Thus a Scyl1/GORAB/Rab6 complex may exist.…”

Section: Discussionmentioning

confidence: 99%

Scyl1 Regulates Golgi Morphology

2010

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BackgroundMembrane trafficking is a defining feature of eukaryotic cells, and is essential for the maintenance of organelle homeostasis and identity. We previously identified Scy1-like 1 (Scyl1), a member of the Scy1-like family of catalytically inactive protein kinases, as a high-affinity binding partner of COPI coats. COPI-coated vesicles control Golgi to endoplasmic reticulum trafficking and we observed that disruption of Scyl1 function leads to a decrease in trafficking of the KDEL receptor via the COPI pathway. We reasoned that if Scyl1 plays a major role in COPI trafficking its disruption could influence Golgi homeostasis.Methodology/Principal FindingsWe performed Scyl1 knock down in cultured cells using previously established methods and observed an alteration in Golgi morphology. Both the surface area and volume of the Golgi is increased in Scyl1-depleted cells, but the continuity and polarity of the organelle is unperturbed. At the ultrastructural level we observe a decrease in the orderly structure of the Golgi with an increase in cisternal luminal width, while the number of Golgi cisternae remains unchanged. The golgin family of proteins forms a detergent resistant network that controls Golgi homeostasis. Disruption of this protein network by knock down of the golgin p115 disrupts the Golgi localization of Scyl1. Moreover, we find that Scyl1 interacts with 58K/formiminotransferase cyclodeaminase (FTCD), a protein that is tightly associated with the cis face of the Golgi.Conclusions/SignificanceOur results place Scyl1 at an interface between the golgin network and COPI trafficking and demonstrate that Scyl1 is required for the maintenance of Golgi morphology. Coupled with the observation from others that Scyl1 is the gene product responsible for the neurodegenerative mouse model mdf, our results additionally implicate the regulation of COPI trafficking and Golgi homeostasis in neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Scyl1 Regulates Golgi Morphology

2010

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“…Mutations in this gene were found to cause Gerodermia osteodysplastica [45,46]. Most of the mutations identified in this gene lead to a loss of protein expression, however in one affected family the mutation still led to protein expression but the function was lost [46]. In all cases no detectable changes in Golgi complex morphology were found.…”

Section: When Function Is Lostmentioning

confidence: 99%

Human Diseases Associated with Form and Function of the Golgi Complex

Bexiga

Simpson

2013

IJMS

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Abstract:The Golgi complex lies at the heart of the secretory pathway and is responsible for modifying proteins and lipids, as well as sorting newly synthesized molecules to their correct destination. As a consequence of these important roles, any changes in its proteome can negatively affect its function and in turn lead to disease. Recently, a number of proteins have been identified, which when either depleted or mutated, result in diseases that affect various organ systems. Here we describe how these proteins have been linked to the Golgi complex, and specifically how they affect either the morphology, membrane traffic or glycosylation ability of this organelle.

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“…This condition is characterized by premature aged appearance, drooping cheeks, maxillary hypoplasia, wrinkled skin, and osteopenia [15]. There is also an oblique furrowing extending from the outer canthus to the lateral border of the supraorbital ridge [19]. Due to the osteopenia, the bones, particularly the vertebrae, are susceptible to fracture [20].…”

Section: Introductionmentioning

confidence: 99%

Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica

Kariminejad

Afroozan

Bozorgmehr

et al. 2017

IJMS

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Cutis laxa is a heterogeneous condition characterized by redundant, sagging, inelastic, and wrinkled skin. The inherited forms of this disease are rare and can have autosomal dominant, autosomal recessive, or X-linked inheritance. Three of the autosomal recessive cutis laxa syndromes, namely cutis laxa IIA (ARCL2A), cutis laxa IIB (ARCL2B), and geroderma osteodysplastica (GO), have very similar clinical features, complicating accurate diagnosis. Individuals with these conditions often present with cutis laxa, progeroid features, and hyperextensible joints. These conditions also share additional features, such as short stature, hypotonia, and congenital hip dislocation, but the severity and frequency of these findings are variable in each of these cutis laxa syndromes. The characteristic features for ARCL2A are abnormal isoelectric focusing and facial features, including downslanting palpebral fissures and a long philtrum. Rather, the clinical phenotype of ARCL2B includes severe wrinkling of the dorsum of the hands and feet, wormian bones, athetoid movements, lipodystrophy, cataract and corneal clouding, a thin triangular face, and a pinched nose. Normal cognition and osteopenia leading to pathological fractures, maxillary hypoplasia, and oblique furrowing from the outer canthus to the lateral border of the supraorbital ridge are discriminative features for GO. Here we present 10 Iranian patients who were initially diagnosed clinically using the respective features of each cutis laxa syndrome. Each patient's clinical diagnosis was then confirmed with molecular Int.

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A novel missense mutation in SCYL1BP1 produces geroderma osteodysplastica phenotype indistinguishable from that caused by nullimorphic mutations

Cited by 31 publications

References 17 publications

Scyl1 Regulates Golgi Morphology

Scyl1 Regulates Golgi Morphology

Human Diseases Associated with Form and Function of the Golgi Complex

Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica

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