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Original article
Mutation in RAB33B, which encodes a regulator of retrograde Golgi transport, defines a second Dyggve–Melchior–Clausen locus
  1. Muneera J Alshammari1,2,
  2. Lefian Al-Otaibi3,
  3. Fowzan S Alkuraya1,2,4
  1. 1Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  2. 2Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh, Saudi Arabia
  3. 3Department of Radiology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  4. 4Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
  1. Correspondence to Dr Fowzan S Alkuraya, Developmental Genetics Unit, King Faisal Specialist Hospital and Research Center, MBC-03 PO Box 3354, Riyad 11211, Saudi Arabia; falkuraya{at}kfshrc.edu.sa

Abstract

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.

  • Vesicle transport
  • skeletal dysplasia
  • Golgi apparatus
  • GTPase
  • guanine nucleotide-binding domain
  • genetics

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Footnotes

  • Funding This study was funded in part by a KACST grant 09-MED941-20 (to FSA) and a Dubai–Harvard Foundation for Medical Research Collaborative Grant (to FSA).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was provided by IRB at KFSHRC.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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