eISSN: 2299-0046
ISSN: 1642-395X
Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii
Current issue Archive Manuscripts accepted About the journal Abstracting and indexing Subscription Contact Instructions for authors
SCImago Journal & Country Rank
vol. 36
Original paper

New variants in COL5A1 gene among Polish patients with Ehlers-Danlos syndrome – analysis of nine cases

Anna Junkiert-Czarnecka, Maria Pilarska-Deltow, Aneta Bąk, Marta Heise, Olga Haus

Adv Dermatol Allergol 2019; XXXVI (1): 29-33
Online publish date: 2019/02/22
View full text
Get citation
JabRef, Mendeley
Papers, Reference Manager, RefWorks, Zotero
The Ehlers-Danlos syndrome (EDS) is a non-inflammatory, heritable connective tissue disorder divided into 13 types according to the 2017 International Classification of the Ehlers-Danlos syndromes. One of the subtypes of EDS, classical (cEDS), is characterized by joint hypermobility, skin hyperextensibility and atrophic scars, which are major criteria of cEDS.

In this study, the first in Central Eastern Europe, 44 patients were investigated. All of them were tested for COL5A1 mutations with direct DNA sequencing.

Material and methods
The study group included 44 patients of Polish origin, all of whom fulfilled criteria for the classical type of Ehlers-Danlos syndrome. Direct sequencing of the COL5A1, COL5A2 and COL1A1 c.934C>T genes was performed for all of them. Evaluation of potential pathogenicity of detected missense mutation was conducted using SIFT (Sorting Intolerant from Tolerant), PolyPhen-2, AlignGVGD (Align Grantham Variance/Grantham Difference). The effect of the splice site mutations was predicted by Human Splicing Finder and NetGene2 tools.

Among all tested patients, nine mutations of COL5A1 gene were detected (8 missense mutations and 1 splice site). The alterations identified by us are new, hitherto not described in other reports. Evaluation of the mutations by in silico tools indicate their pathogenicity.

Our study is the first COL5A1 gene molecular investigation conducted among cEDS patients from Central Eastern Europe. Besides new COL5A1 variant findings, we gained molecular confirmation of clinical diagnosis of cEDS. In some cases, specific and adequate evaluation and classification of EDS patients based only on clinical features, may be difficult.


Ehlers-Danlos syndrome, mutation, collagen, connective tissue, Polish population

Malfait F, De Paepe A. Molecular genetics in classic Ehlers-Danlos syndrome. Am J Med Genet 2005; 139C: 17-23.
Malfait F, Wenstrup R, De Paepe A. Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type. Genet Med 2010; 12: 597-605.
Michalickova K, Susic M, Willing MC, et al. Mutations of the alpha2(V) chain of type V collagen impair matrix assembly and produce Ehlers-Danlos syndrome type I. Hum Mol Genet 1998; 7: 249-55.
Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet 2017; 175: 8-26.
Beighton P, De Paepe A, Steinmann B, et al. Ehlers-Danlos syndromes: revised nosology, Villefranche 1997. Am J Med Genet 1998; 77: 31-7.
Symoens S, Syx D, Malfait F, et al. Comprehensive molecular analysis demonstrates type V collagen mutations in over 90% of patients with classic EDS and allows to refine diagnostic criteria. Hum Mutat 2010; 10: 1485-93.
Birk DE. Type V collagen: heterotypic type I/V collagen interactions in the regulation of fibril assembly. Micron 2001; 32: 223-37.
Takahara K, Hoffman GG, Greenspan DS. Complete structural organization of the human alpha 1 (V) collagen gene (COL5A1): divergence from the conserved organization of other characterized fibrillar collagen genes. Genomics 1995; 29: 588-97.
Mitchell AL, Schwarze U, Jennings JF, Byers PH. Molecular mechanisms of classical Ehlers-Danlos syndrome (EDS). Hum Mutat 2009; 30: 995-1002.
Paladin L, Tosatto SC, Minervini G. Structural in silico dissection of the collagen V interactome to identify genotype-phenotype correlations in classic Ehlers-Danlos syndrome (EDS). FEBS Lett 2005; 589: 3871-8.
Ritelli M, Dordoni C, Venturini M, et al. Clinical and molecular characterization of 40 patients with classic Ehlers-Danlos syndrome: identification of 18 COL5A1 and 2 COL5A2 novel mutations. Orphanet J Rare Dis 2013; 8: 58.
Takahara K, Schwarze U, Imamura Y, et al. Order of intron removal influences multiple splice outcomes, including a two-exon skip, in a COL5A1 acceptor-site mutation that results in abnormal pro-alpha1(V) N-propeptides and Ehlers-Danlos syndrome type I. Am J Hum Genet 2002; 71: 451-65.
Symoens S, Malfait F, Vlummens P, et al. A novel splice variant in the N-propeptide of COL5A1 causes an EDS phenotype with severe kyphoscoliosis and eye involvement. PLoS One 2011; 6: e20121.
Wenstrup R, Florer J, Brunskill E, et al. Type V collagen controls the initiation of collagen fibril assembly. J Biol Chem 2004; 279: 53331-37.
Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 2009; 4: 1073-81.
Tavtigian SV, Deffenbaugh AM, Yin L, et al. Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral. J Med Genet 2006; 43: 295-305.
Giunta C, Nuytinck L, Raghunath M, et al. Homozygous Gly530Ser substitution in COL5A1 causes mild classical Ehlers-Danlos syndrome. Am J Med Genet 2002; 109: 284-90.
Malfait F, Coucke P, Symoens S, et al. The molecular basis of classic Ehlers-Danlos syndrome: a comprehensive study of biochemical and molecular findings in 48 unrelated patients. Hum Mutat 2005; 25: 28-37.
Symoens S, Renard M, Bonod-Bidaud C, et al. Identification of binding partners interacting with the alpha1-N-propeptide of type V collagen. Biochem J 2011; 433: 371-81.
Quick links
© 2019 Termedia Sp. z o.o. All rights reserved.
Developed by Bentus.
PayU - płatności internetowe