Mutation in RAB33B, which encodes a regulator of retrograde Golgi transport, defines a second Dyggve-Melchior-Clausen locus

Background 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. Methods 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. Results 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. Conclusion This study identifies a new DMC gene and highlights the role of intracellular traffic in the pathogenesis of this disease.