Molecular Genetics of Ehlers–Danlos Syndrome

Abstract

Ehlers–Danlos syndrome (EDS) subsumes a clinically and genetically heterogeneous group of rare connective tissue diseases, characterised by tissue fragility and a highly variable clinical spectrum involving skin, ligaments, joints, blood vessels and internal organs. Based on clinical criteria as well as genetic and biochemical data, the current Villefranche classification subdivides EDS into six major subtypes, which are caused by mutations in genes encoding fibrillar collagens or enzymes involved in collagen biosynthesis. Mutations in type V and type III collagen cause classic and vascular EDS, respectively, whereas mutations affecting the processing of type I collagen lead to the kyphoscoliotic, arthrochalasic and dermatosparactic EDS types. During the last years, specific biochemical and molecular investigations identified several new EDS variants and have brought new insights into the molecular pathogenesis of EDS. Establishing the correct EDS subtype has important implications for genetic counselling and management and offers the opportunity for clinical trials, which are still at the beginning.

Key Concepts:

  • EDS is a clinically and genetically heterogeneous group of connective tissue diseases.

  • The Villefranche classification distinguishes six major EDS subtypes.

  • The most frequent molecular causes in EDS are mutations in fibrillar collagens or enzymes involved in collagen metabolism.

  • Recent and ongoing research is leading to the discovery of new EDS variants and to an improvement of understanding the molecular pathology of EDS.

  • Defining the EDS subtype has an important value for the patient and is the basis for clinical management and possible future clinical trials.

Keywords: EDS; connective tissue; collagen; classic; hypermobile; vascular; kyphoscoliotic; arthrochalatic; dermatosparactic

Figure 1.

Schematic representation of the fibrillar collagens.

Figure 2.

Mutations in collagens and collagen‐modifying enzymes affect collagen biosynthesis at different stages and lead to various EDS subtypes (a) reduced synthesis of procollagen α1(V) and α2(V) leads to EDS classic type in 60–85% of mutation positive patients. (b) Defective hydroxylation of lysyl residues in (Gly‐Xaa‐Lys) triplets of type I collagen lead to EDS kyphoscoliotic type. (c) Intracellular storage and impaired secretion of structural altered type III collagen chains leads to EDS vascular type (d) retention of the N‐propeptide in the mature α1(I) and α2(I) molecules (1) through loss of the procollagen I N‐proteinase cleavage site in COL1A1 or COL1A2 leads to EDS arthrochalasic type; (2) through procollagen I N‐proteinase deficiency causes exclusively uncleaved pNa1(I) and pNa2(I) collagen chains and leads to EDS dermatosparactic type. (e) Aberrant fibril formation through structurally abnormal type V collagen leads to EDS classic type in a minority of patients. (f) Impaired interaction with proteins of the extracellular matrix (e.g. tenascin‐X) lead to other EDS subtypes.

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Further Reading

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Levy HP (2010) Ehlers–Danlos Syndrome, Hypermobility Type. 2004 Oct 22 [updated 2012 Sep 13]. In: Pagon RA, Bird TD, Dolan CR et al. (eds) GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle.

Malfait F, Wenstrup R and De Paepe A (2011) Ehlers–Danlos Syndrome, Classic Type. 2007 May 29 [Updated 2011 Aug 18]. In: Pagon RA, Bird TD, Dolan CR et al. (eds) GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle.

Pepin MG and Byers PH (2011) Ehlers–Danlos Syndrome Type IV. 1999 Sep 2 [Updated 2011 May 3]. In: Pagon RA, Bird TD, Dolan CR et al. (eds) GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle.

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Mayer, Karin(Nov 2012) Molecular Genetics of Ehlers–Danlos Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024295]