Biallelic B3GALT6 mutations cause spondylodysplastic Ehlers-Danlos syndrome

Tim Van Damme, Xiaomeng Pang, Brecht Guillemyn, Sandrine Gulberti, Delfien Syx, Riet De Rycke, Olivier Kaye, Christine E. M. de Die-Smulders, Rolph Pfundt, Ariana Kariminejad, Sheela Nampoothiri, Genevieve Pierquin, Saskia Bulk, Austin A. Larson, Kathryn C. Chatfield, Marleen Simon, Anne Legrand, Marion Gerard, Sofie Symoens, Sylvie Fournel-Gigleux*Fransiska Malfait*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

20 Citations (Web of Science)

Abstract

Proteoglycans are among the most abundant and structurally complex biomacromolecules and play critical roles in connective tissues. They are composed of a core protein onto which glycosaminoglycan (GAG) side chains are attached via a linker region. Biallelic mutations in B3GALT6, encoding one of the linker region glycosyltransferases, are known to cause either spondyloepimetaphyseal dysplasia (SEMD) or a severe pleiotropic form of Ehlers-Danlos syndromes (EDS). This study provides clinical, molecular and biochemical data on 12 patients with biallelic B3GALT6 mutations. Notably, all patients have features of both EDS and SEMD. In addition, some patients have severe and potential life-threatening complications such as aortic dilatation and aneurysm, cervical spine instability and respiratory insufficiency. Whole-exome sequencing, next generation panel sequencing and direct sequencing identified biallelic B3GALT6 mutations in all patients. We show that these mutations reduce the amount of beta 3GalT6 protein and lead to a complete loss of galactosyltransferase activity. In turn, this leads to deficient GAG synthesis, and ultrastructural abnormalities in collagen fibril organization. In conclusion, this study redefines the phenotype associated with B3GALT6 mutations on the basis of clinical, molecular and biochemical data in 12 patients, and provides an in-depth assessment of beta 3GaIT6 activity and GAG synthesis to better understand this rare condition.

Original languageEnglish
Pages (from-to)3475-3487
Number of pages13
JournalHuman Molecular Genetics
Volume27
Issue number20
DOIs
Publication statusPublished - 15 Oct 2018

Keywords

  • DESBUQUOIS DYSPLASIA
  • XYLT1 MUTATIONS
  • SKELETAL DYSPLASIA
  • HEPARAN-SULFATE
  • B3GAT3 MUTATION
  • BONE FRAGILITY
  • PROTEOGLYCAN
  • SPECTRUM
  • PATIENT
  • IMAGE

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