Murine model of the Ehlers-Danlos syndrome: col5a1 haploinsufficiency disrupts collagen fibril assembly at multiple stages

Richard J. Wenstrup, Jane B. Florer, Jeffrey M. Davidson, Charlotte L. Phillips, Brent Pfeiffer, Diana W. Menezes, Inna Chervoneva, David E. Birk

Research output: Contribution to journalArticle

95 Citations (Scopus)

Abstract

The most commonly identified mutations causing Ehlers-Danlos syndrome (EDS) classic type result in haploinsufficiency of proα1(V) chains of type V collagen, a quantitatively minor collagen that co-assembles with type I collagen as heterotypic fibrils. To determine the role(s) of type I/V collagen interactions in fibrillogenesis and elucidate the mechanism whereby half-reduction of type V collagen causes abnormal connective tissue biogenesis observed in EDS, we analyzed mice heterozygous for a targeted inactivating mutation in col5a1 that caused 50% reduction in col5a1 mRNA and collagen V. Comparable with EDS patients, they had decreased aortic stiffness and tensile strength and hyperextensible skin with decreased tensile strength of both normal and wounded skin. In dermis, 50% fewer fibrils were assembled with two subpopulations: relatively normal fibrils with periodic immunoreactivity for collagen V where type I/V interactions regulate nucleation of fibril assembly and abnormal fibrils, lacking collagen V, generated by unregulated sequestration of type I collagen. The presence of the aberrant fibril subpopulation disrupts the normal linear and lateral growth mediated by fibril fusion. Therefore, abnormal fibril nucleation and dysfunctional fibril growth with potential disruption of cell-directed fibril organization leads to the connective tissue dysfunction associated with EDS.

Original languageEnglish
Pages (from-to)12888-12895
Number of pages8
JournalJournal of Biological Chemistry
Volume281
Issue number18
DOIs
StatePublished - May 5 2006
Externally publishedYes

Fingerprint

Ehlers-Danlos Syndrome
Haploinsufficiency
Collagen Type V
Collagen Type I
Collagen
Tensile Strength
Connective Tissue
Skin
Nucleation
Tensile strength
Tissue
Mutation
Vascular Stiffness
Dermis
Growth
Fusion reactions
Stiffness
Messenger RNA

ASJC Scopus subject areas

  • Biochemistry

Cite this

Murine model of the Ehlers-Danlos syndrome : col5a1 haploinsufficiency disrupts collagen fibril assembly at multiple stages. / Wenstrup, Richard J.; Florer, Jane B.; Davidson, Jeffrey M.; Phillips, Charlotte L.; Pfeiffer, Brent; Menezes, Diana W.; Chervoneva, Inna; Birk, David E.

In: Journal of Biological Chemistry, Vol. 281, No. 18, 05.05.2006, p. 12888-12895.

Research output: Contribution to journalArticle

Wenstrup, RJ, Florer, JB, Davidson, JM, Phillips, CL, Pfeiffer, B, Menezes, DW, Chervoneva, I & Birk, DE 2006, 'Murine model of the Ehlers-Danlos syndrome: col5a1 haploinsufficiency disrupts collagen fibril assembly at multiple stages', Journal of Biological Chemistry, vol. 281, no. 18, pp. 12888-12895. https://doi.org/10.1074/jbc.M511528200
Wenstrup, Richard J. ; Florer, Jane B. ; Davidson, Jeffrey M. ; Phillips, Charlotte L. ; Pfeiffer, Brent ; Menezes, Diana W. ; Chervoneva, Inna ; Birk, David E. / Murine model of the Ehlers-Danlos syndrome : col5a1 haploinsufficiency disrupts collagen fibril assembly at multiple stages. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 18. pp. 12888-12895.
@article{0249f012fa56475a8e0ef577ff7f0441,
title = "Murine model of the Ehlers-Danlos syndrome: col5a1 haploinsufficiency disrupts collagen fibril assembly at multiple stages",
abstract = "The most commonly identified mutations causing Ehlers-Danlos syndrome (EDS) classic type result in haploinsufficiency of proα1(V) chains of type V collagen, a quantitatively minor collagen that co-assembles with type I collagen as heterotypic fibrils. To determine the role(s) of type I/V collagen interactions in fibrillogenesis and elucidate the mechanism whereby half-reduction of type V collagen causes abnormal connective tissue biogenesis observed in EDS, we analyzed mice heterozygous for a targeted inactivating mutation in col5a1 that caused 50{\%} reduction in col5a1 mRNA and collagen V. Comparable with EDS patients, they had decreased aortic stiffness and tensile strength and hyperextensible skin with decreased tensile strength of both normal and wounded skin. In dermis, 50{\%} fewer fibrils were assembled with two subpopulations: relatively normal fibrils with periodic immunoreactivity for collagen V where type I/V interactions regulate nucleation of fibril assembly and abnormal fibrils, lacking collagen V, generated by unregulated sequestration of type I collagen. The presence of the aberrant fibril subpopulation disrupts the normal linear and lateral growth mediated by fibril fusion. Therefore, abnormal fibril nucleation and dysfunctional fibril growth with potential disruption of cell-directed fibril organization leads to the connective tissue dysfunction associated with EDS.",
author = "Wenstrup, {Richard J.} and Florer, {Jane B.} and Davidson, {Jeffrey M.} and Phillips, {Charlotte L.} and Brent Pfeiffer and Menezes, {Diana W.} and Inna Chervoneva and Birk, {David E.}",
year = "2006",
month = "5",
day = "5",
doi = "10.1074/jbc.M511528200",
language = "English",
volume = "281",
pages = "12888--12895",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "18",

}

TY - JOUR

T1 - Murine model of the Ehlers-Danlos syndrome

T2 - col5a1 haploinsufficiency disrupts collagen fibril assembly at multiple stages

AU - Wenstrup, Richard J.

AU - Florer, Jane B.

AU - Davidson, Jeffrey M.

AU - Phillips, Charlotte L.

AU - Pfeiffer, Brent

AU - Menezes, Diana W.

AU - Chervoneva, Inna

AU - Birk, David E.

PY - 2006/5/5

Y1 - 2006/5/5

N2 - The most commonly identified mutations causing Ehlers-Danlos syndrome (EDS) classic type result in haploinsufficiency of proα1(V) chains of type V collagen, a quantitatively minor collagen that co-assembles with type I collagen as heterotypic fibrils. To determine the role(s) of type I/V collagen interactions in fibrillogenesis and elucidate the mechanism whereby half-reduction of type V collagen causes abnormal connective tissue biogenesis observed in EDS, we analyzed mice heterozygous for a targeted inactivating mutation in col5a1 that caused 50% reduction in col5a1 mRNA and collagen V. Comparable with EDS patients, they had decreased aortic stiffness and tensile strength and hyperextensible skin with decreased tensile strength of both normal and wounded skin. In dermis, 50% fewer fibrils were assembled with two subpopulations: relatively normal fibrils with periodic immunoreactivity for collagen V where type I/V interactions regulate nucleation of fibril assembly and abnormal fibrils, lacking collagen V, generated by unregulated sequestration of type I collagen. The presence of the aberrant fibril subpopulation disrupts the normal linear and lateral growth mediated by fibril fusion. Therefore, abnormal fibril nucleation and dysfunctional fibril growth with potential disruption of cell-directed fibril organization leads to the connective tissue dysfunction associated with EDS.

AB - The most commonly identified mutations causing Ehlers-Danlos syndrome (EDS) classic type result in haploinsufficiency of proα1(V) chains of type V collagen, a quantitatively minor collagen that co-assembles with type I collagen as heterotypic fibrils. To determine the role(s) of type I/V collagen interactions in fibrillogenesis and elucidate the mechanism whereby half-reduction of type V collagen causes abnormal connective tissue biogenesis observed in EDS, we analyzed mice heterozygous for a targeted inactivating mutation in col5a1 that caused 50% reduction in col5a1 mRNA and collagen V. Comparable with EDS patients, they had decreased aortic stiffness and tensile strength and hyperextensible skin with decreased tensile strength of both normal and wounded skin. In dermis, 50% fewer fibrils were assembled with two subpopulations: relatively normal fibrils with periodic immunoreactivity for collagen V where type I/V interactions regulate nucleation of fibril assembly and abnormal fibrils, lacking collagen V, generated by unregulated sequestration of type I collagen. The presence of the aberrant fibril subpopulation disrupts the normal linear and lateral growth mediated by fibril fusion. Therefore, abnormal fibril nucleation and dysfunctional fibril growth with potential disruption of cell-directed fibril organization leads to the connective tissue dysfunction associated with EDS.

UR - http://www.scopus.com/inward/record.url?scp=33744949552&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33744949552&partnerID=8YFLogxK

U2 - 10.1074/jbc.M511528200

DO - 10.1074/jbc.M511528200

M3 - Article

C2 - 16492673

AN - SCOPUS:33744949552

VL - 281

SP - 12888

EP - 12895

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 18

ER -