Biallelic B3GALT6 mutations cause spondylodysplastic Ehlers-Danlos syndrome.

[en] 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 beta3GalT6 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 beta3GalT6 activity and GAG synthesis to better understand this rare condition.

Disciplines :

Genetics & genetic processes

Author, co-author :

Van Damme, Tim

Pang, Xiaomeng

Guillemyn, Brecht

Gulberti, Sandrine

Syx, Delfien

De Rycke, Riet

Kaye, Olivier

de Die-Smulders, Christine E. M.

Pfundt, Rolph

Kariminejad, Ariana

More authors (11 more)

Language :

English

Title :

Biallelic B3GALT6 mutations cause spondylodysplastic Ehlers-Danlos syndrome.

Publication date :

2018

Journal title :

Human Molecular Genetics

ISSN :

0964-6906

eISSN :

1460-2083

Publisher :

Oxford University Press, United Kingdom

Volume :

Issue :

Pages :

3475-3487

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 07 January 2019

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