Alshammari, M. J., Al-Otaibi, L. & Alkuraya, F. S. Mutation in RAB33B, which encodes a regulator of retrograde Golgi transport, defines a second Dyggve-Melchior-Clausen locus. J. Med. Genet. 49, 455-461

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Journal of Medical Genetics (Impact Factor: 6.34). 05/2012; 49(7):455-61. DOI: 10.1136/jmedgenet-2011-100666
Source: PubMed


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: 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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