Mutation in<i>RAB33B</i>, which encodes a regulator of retrograde Golgi transport, defines a second Dyggve–Melchior–Clausen locus

Alshammari, Muneera; Al-Otaibi, Lefian; Alkuraya, Fowzan S.

doi:10.1136/jmedgenet-2011-100666

Cited by 35 publications

(44 citation statements)

References 24 publications

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“…Two missense mutations in the GTPase domain of RAB33B have been identified in patients with two different skeletal dysplasias. Interestingly in Dyggve-Melchior-Clausen disease no changes were detected at the level of the Golgi complex [41], whereas in Smith-McCort Dysplasia reduced RAB33B protein expression levels were correlated with a swollen and fragmented Golgi complex [14]. Another observation is that the mutation found in Dyggve-Melchior-Clausen disease occurs at a lysine residue that is conserved in RAB33B orthologs across all species [41].…”

Section: When Function Is Lostmentioning

confidence: 99%

“…Interestingly in Dyggve-Melchior-Clausen disease no changes were detected at the level of the Golgi complex [41], whereas in Smith-McCort Dysplasia reduced RAB33B protein expression levels were correlated with a swollen and fragmented Golgi complex [14]. Another observation is that the mutation found in Dyggve-Melchior-Clausen disease occurs at a lysine residue that is conserved in RAB33B orthologs across all species [41]. In fact, this lysine residue is found in the GTP binding pocket of all Rab family members thereby demonstrating the importance of this residue to the function of the protein.…”

Section: When Function Is Lostmentioning

confidence: 99%

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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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Section: When Function Is Lostmentioning

confidence: 99%

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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“…In addition, the absence of mutation in DYM in a well‐characterized SMC patient had led us to hypothesize a possible genetic heterogeneity of the disease [Neumann et al, ]. In support of this hypothesis, Alshammari and colleagues have recently identified a missense mutation (p.K46Q) in a new gene, RAB33B , using autozygosity mapping and exome sequencing in a large consanguineous Saudi family [Alshammari et al, ]. RAB33B (MIM# 605950) belongs to the large Rab family of small GTP‐binding proteins that play important roles at defined steps of vesicular transport in protein secretion and the endocytosis pathway [Barr and Lambright, ; Stenmark and Olkkonen, ; Zheng et al, ].…”

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confidence: 99%

A NovelRAB33BMutation in Smith-McCort Dysplasia

et al. 2012

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Smith-McCort dysplasia (SMC) is a rare autosomal recessive spondylo-epi-metaphyseal dysplasia with skeletal features identical to those of Dyggve-Melchior-Clausen syndrome (DMC) but with normal intelligence and no microcephaly. Although both syndromes were shown to result from mutations in the DYM gene, which encodes the Golgi protein DYMECLIN, a few SMC patients remained negative in DYM mutation screening. Recently, autozygosity mapping and exome sequencing in a large SMC family have allowed the identification of a missense mutation in RAB33B, another Golgi protein involved in retrograde transport of Golgi vesicles. Here, we report a novel RAB33B mutation in a second SMC case that leads to a marked reduction of the protein as shown by Western blot and immunofluorescence. These data confirm the genetic heterogeneity of SMC dysplasia and highlight the role of Golgi transport in the pathogenesis of SMC and DMC syndromes.

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“…We successfully observed failure to complement for the two disease associated variants, P219S and K46Q [41, 42]. Interestingly, both non-disease-annotated variants, P142L (rs369719131) and T177M (rs140381459), also showed loss of complementation.…”

Section: Discussionmentioning

confidence: 99%

Identifying pathogenicity of human variants via paralog-based yeast complementation

et al. 2017

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To better understand the health implications of personal genomes, we now face a largely unmet challenge to identify functional variants within disease-associated genes. Functional variants can be identified by trans-species complementation, e.g., by failure to rescue a yeast strain bearing a mutation in an orthologous human gene. Although orthologous complementation assays are powerful predictors of pathogenic variation, they are available for only a few percent of human disease genes. Here we systematically examine the question of whether complementation assays based on paralogy relationships can expand the number of human disease genes with functional variant detection assays. We tested over 1,000 paralogous human-yeast gene pairs for complementation, yielding 34 complementation relationships, of which 33 (97%) were novel. We found that paralog-based assays identified disease variants with success on par with that of orthology-based assays. Combining all homology-based assay results, we found that complementation can often identify pathogenic variants outside the homologous sequence region, presumably because of global effects on protein folding or stability. Within our search space, paralogy-based complementation more than doubled the number of human disease genes with a yeast-based complementation assay for disease variation.

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Mutation inRAB33B, which encodes a regulator of retrograde Golgi transport, defines a second Dyggve–Melchior–Clausen locus

Abstract: This study identifies a new DMC gene and highlights the role of intracellular traffic in the pathogenesis of this disease.

Cited by 35 publications

References 24 publications

Human Diseases Associated with Form and Function of the Golgi Complex

Human Diseases Associated with Form and Function of the Golgi Complex

A NovelRAB33BMutation in Smith-McCort Dysplasia

Identifying pathogenicity of human variants via paralog-based yeast complementation

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