Mutation in RAB33B, which encodes a regulator of retrograde Golgi transport, defines a second Dyggve--Melchior--Clausen locus.
ABSTRACT Dyggve--Melchior--Clausen syndrome (DMC) is a chondrodysplasia that bears significant phenotypic resemblance to mucopolysaccharidosis type IV (Morquio disease). Autosomal recessive mutations in DYM are known to cause this disease through its role in Golgi organisation and intracellular traffic, but genetic heterogeneity is suspected.
A family with DMC and normal intellectual development underwent clinical evaluation followed by autozygosity mapping and exome sequencing. Immunoblot and immunofluorescence analyses were performed to characterise the effect of the mutation.
This multiplex consanguineous family links to a novel locus on 4q31.1. Exome sequencing revealed a missense mutation in RAB33B, which encodes a Rab protein with an established role in retrograde Golgi traffic. The mutation qualitatively replaces the invariant lysine residue in the guanine nucleotide-binding domain of this small GTPase protein and leads to marked protein deficiency, making it the likely causative mutation of DMC in this family.
This study identifies a new DMC gene and highlights the role of intracellular traffic in the pathogenesis of this disease.
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ABSTRACT: Autozygosity, or the inheritance of two copies of an ancestral allele, has the potential to not only reveal phenotypes caused by biallelic mutations in autosomal recessive genes, but to also facilitate the mapping of such mutations by flagging the surrounding haplotypes as tractable runs of homozygosity (ROH), a process known as autozygosity mapping. Since SNPs replaced microsatellites as markers for the purpose of genomewide identification of ROH, autozygosity mapping of Mendelian genes has witnessed a significant acceleration. Historically, successful mapping traditionally required favorable family structure that permits the identification of an autozygous interval that is amenable to candidate gene selection and confirmation by Sanger sequencing. This requirement presented a major bottleneck that hindered the utilization of simplex cases and many multiplex families with autosomal recessive phenotypes. However, the advent of next-generation sequencing that enables massively parallel sequencing of DNA has largely bypassed this bottleneck and thus ushered in an era of unprecedented pace of Mendelian disease gene discovery. The ability to identify a single causal mutation among a massive number of variants that are uncovered by next-generation sequencing can be challenging, but applying autozygosity as a filter can greatly enhance the enrichment process and its throughput. This review will discuss the power of combining the best of both techniques in the mapping of recessive disease genes and offer some tips to troubleshoot potential limitations.Human Genetics 08/2013; · 4.63 Impact Factor
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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.International Journal of Molecular Sciences 01/2013; 14(9):18670-81. · 2.46 Impact Factor