Vanakker, Olivier

Frontiers in Genetics

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Olivier M. Vanakker

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EDITORIAL
published: 01 November 2013
doi: 10.3389/fgene.2013.00207
Coordinated orphan disease research: yes, we can!
Olivier M. Vanakker*
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
*Correspondence: olivier.vanakker@ugent.be
Edited by:
Raina Robeva, Sweet Briar College, USA
Keywords: pseudoxanthoma elasticum, ectopic mineralization, ABCC6, orphan disease, connective tissue diseases, ENPP1
Research in the field of orphan diseases is confronted with several
hurdles. Not only lack of knowledge and insufficient awareness
for these disorders among the general public, politicians and
yes, often also among the medical and scientific community, but
also limited funding, dispersed research initiatives and seemingly
unrelated datasets usually make it more difficult to progress in the
understanding of these disorders. Ectopic mineralization diseases,
with pseudoxanthoma elasticum (PXE) as a paradigm disorder,
have been no exception to the rule in facing all of these hurdles.
But at the same time, PXE has been a prime example of the efforts
to overcome these barriers. And to a certain point, they can be
overcome as this Special Topic of Frontiers in Systems Biology
proves.
Soft tissue mineralization is the result of a delicate interplay
of a large number of protagonists—transcription factors, calci-
fication promoting and inhibiting proteins and enzymes, home-
ostatic cues (Schinke et al., 1999). It is precisely this complexity
that makes soft tissue calcification so difficult to comprehend. At
the same time, it is the prototype of a pathophysiological mech-
anism that cries out for a concerted action of different fields of
expertise to build our insights into how it functions. Indeed, there
are many faces to soft tissue mineralization, several of which are
captured in PXE. This rare autosomal recessive connective tis-
sue disorder is characterized by ocular, skin, and cardiovascular
symptoms and can present important variability, particularly in
the severity of symptoms (Vanakker et al., 2008). The histological
hallmark of PXE is mineralization and fragmentation of elastic
fibers. PXE was shown to be caused by mutations in the ABCC6
gene, encoding an ATP-dependent transporter protein, though
the physiological role and pathological consequences of ABCC6
remain unclear (Le Saux et al., 2001).
To achieve the ultimate goal of our research, a treatment to
stabilize or cure PXE, there is a need to understand the function
of the ABCC6 protein which is perturbed in PXE. Despite the
considerable progress made in the past years, which is reflected
on in this issue, many crucial questions remain unanswered.
Concerted action also implies that we can look beyond our own
protein of interest to other related proteins and diseases; their
story—the difficulties as much as the successes—may give us
valuable insights in how we can proceed in understanding our
ABC-transporter of interest.
Next to mechanistic insights, the phenotype of patients should
be defined in the greatest detail. The importance of this for the
follow-up of patients goes without saying but cannot be seen
independently of our quest to understand the mechanisms of dis-
ease. In this respect, recent findings on the unique characteristics
of the PXE vasculopathy and advances in the ophthalmological
features of PXE can give us important clues for the mechanisms
that lie beneath (De Zaeytijd et al., 2010; Lefthériotis et al., 2011;
Campens et al., 2013).
Finally, the molecular biology of these disorders needs be
further refined. More than a decade after the identification of
ABCC6 as the causal gene for PXE, the molecular basis of PXE
has become increasingly more complex then was initially con-
ceived. Not only have a number of genes been identified which
are associated with similar phenotypes, such as GGCX or ENPP1,
but the variability of the PXE phenotype has also triggered the
search for modifier genes (Vanakker et al., 2007; Nitschke et al.,
2012). Though until now most of the secondary genes with a
link to the phenotype should be considered susceptibility fac-
tors in stead of true modifiers, prudent progress has been made
through the characterization of the role of VEGF-A variants in
ocular neovascularization (Zarbock et al., 2009).
The drive behind research endeavors aiming to understand
a group of rare disorders is the result of the enthusiasm of
a group of dedicated scientists but—no less—also of patients
and their representing organizations. Despite the use of ani-
mal models which can be very valuable for certain aspects of
disease, the active involvement of patients in research, compris-
ing clinical studies and experiments on tissues, remains invalu-
able for the future of PXE research. The advocacy groups of
these patients play an important role in translating research
findings to the patients but have often also been a thriving
force to gather and stimulate researchers and physicians around
the world.
In this special topic of Frontiers in Systems Biology, some
of the leading scientists and physicians in the field of PXE and
ectopic mineralization disorders have summarized the current
knowledge in their particular field of expertise and share their
thoughts on how further progress can bemade. Basic science con-
tributions cover the complexity of ABCC6 transporter function
in (patho)physiological mineralization, the role of mesenchymal
cells such as fibroblasts and mechanisms of remodeling in cal-
cified vasculopathies. A perspective on the relevance of other
ABC transporters for the study of ABCC6 and a methodologi-
cal review on one of the innovative model organisms, the Danio
Rerio or zebrafish, provide a balance between current and future
endeavors. The molecular etiology is covered by reviews on the
transcriptional regulation of the ABCC6 gene and the role of
modifier genes in PXE, while a contribution on ENPP1 and the
overlapping phenotype between PXE and Generalized Arterial
Calcification of Infancy (GACI) makes the transition to clinical
papers on specific aspects of the PXE retinopathy and vascu-
lopathy. This research topic concludes with a perspective on the
www.frontiersin.org November 2013 | Volume 4 | Article 207 | 1
Vanakker Coordinated orphan disease research
current and future role of advocacy groups in orphan disease
research.
The rarity of hereditary soft tissue mineralization disorders
require a coordinated effort at all levels mentioned above to
obtain faster advances in knowledge of disease pathophysiol-
ogy and its rapid translation into the clinic. This will inevitably
improve health care for patients suffering from these orphan dis-
eases, but may also lead to valuable insights on more common
disorders such as atherosclerosis and stroke as well as on the pro-
cess of aging. Though maybe not always obvious at first sight,
there is thus, unquestionably a relation with some of the global
health care problems the world is facing today and will continue
to face in the future. This Special Topic evidences how the work
of several research groups on rare mineralization diseases can be
brought together to reflect what is currently living in the field. At
the same time, it should be an incentive to work further on a plat-
form to integrate the research findings in these diseases retro- and
prospectively. Only by uniting our attempts to gain insights in the
complexity of soft tissue mineralization will we be able to get a
grip on these diseases.
REFERENCES
Campens, L., Vanakker, O. M., Trachet, B., Segers, P., Leroy, B. P., De Zaeytijd,
J., et al. (2013). Characterization of cardiovascular involvement in pseudox-
anthoma elasticum families. Ather. Thromb. Vasc. Biol. 33, 2646–2652. doi:
10.1161/ATVBAHA.113.301901
De Zaeytijd, J., Vanakker, O. M., Coucke, P. J., De Paepe, A., De Laey, J. J, and
Leroy, B. P. (2010). Added value of infrared, red-free and autofluorescence fun-
cus imaging in pseudoxanthoma elasticum. Br. J. Ophthalmol. 94, 479–486. doi:
10.1136/bjo.2009.162644
Lefthériotis, G., Abraham, P., Le Corre, Y., Le Saux, O., Henrion, D., Ducluzeau,
P. H., et al. (2011). Relationship between ankle brachial index and arterial
remodeling in pseudoxanthoma elasticum. J. Vasc. Surg. 54, 1390–1394. doi:
10.1016/j.jvs.2011.04.041
Le Saux, O., Beck, K., Sachsinger, C., Silvestri, C., Treiber, C., Göring, H. H., et al.
(2001). A spectrum of ABCC6 mutations is responsible for pseudoxanthoma
elasticum. Am. J. Hum. Genet. 69, 749–764. doi: 10.1086/323704
Nitschke, Y., Baujat, G., Botschen, U., Wittkampf, T., du Moulin, M., Stella, J., et al.
(2012). Generalized arterial calcification of infancy and pseudoxanthoma elas-
ticum can be caused by mutations in either ENPP1 or ABCC6. Am. J. Hum.
Genet. 90, 25–39. doi: 10.1016/j.ajhg.2011.11.020
Schinke, T., McKee, M. D., and Karsenty, G. (1999). Extracellular matrix calcifica-
tion: where is the action? Nat. Genet. 21, 225–229.
Vanakker, O.M., Leroy, B. P., Coucke, P., Bercovitch, L. G., Uitto, J., Viljoen, D., et al.
(2008). Novel clinico-molecular insights in pseudoxanthoma elasticum pro-
vide an efficient molecular screening method and a comprehensive diagnostic
flowchart. Hum. Mut. 29:205. doi: 10.1002/humu.9514
Vanakker, O. M., Martin, L., Gheduzzi, D., Leroy, B. P., Loeys, B. L.,
Guerci, V. I., et al. (2007). Pseudoxanthoma elasticum-like phenotype with
cutis laxa and multiple coagulation factor deficiency represents a sepa-
rate genetic entity. J. Invest. Dermatol. 127, 581–587. doi: 10.1038/sj.jid.
5700610
Zarbock, R., Hendig, D., Szlsika, C., Kleesiek, K., and Gotting, C. (2009). Vascular
endothelial growth facyor gene polymorphisms as prognostic markers for
ocular manifestations in pseudoxanthoma elasticum. Hum. Mol. Genet. 18,
3344–3351. doi: 10.1093/hmg/ddp259
Received: 24 September 2013; accepted: 27 September 2013; published online: 01
November 2013.
Citation: Vanakker OM (2013) Coordinated orphan disease research: yes, we can!
Front. Genet. 4:207. doi: 10.3389/fgene.2013.00207
This article was submitted to Systems Biology, a section of the journal Frontiers in
Genetics.
Copyright © 2013 Vanakker. This is an open-access article distributed under the
terms of the Creative Commons Attribution License (CC BY). The use, distribution or
reproduction in other forums is permitted, provided the original author(s) or licensor
are credited and that the original publication in this journal is cited, in accordance with
accepted academic practice. No use, distribution or reproduction is permitted which
does not comply with these terms.
Frontiers in Genetics | Systems Biology November 2013 | Volume 4 | Article 207 | 2


Coordinated orphan disease research: yes, we can!

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Ghent University Academic Bibliography

EDITORIALpublished: 01 November 2013doi: 10.3389/fgene.2013.00207Coordinated orphan disease research: yes, we can!Olivier M. Vanakker*Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium*Correspondence: olivier.vanakker@ugent.beEdited by:Raina Robeva, Sweet Briar College, USAKeywords: pseudoxanthoma elasticum, ectopic mineralization, ABCC6, orphan disease, connective tissue diseases, ENPP1Research in the field of orphan diseases is confronted with severalhurdles. Not only lack of knowledge and insufficient awarenessfor these disorders among the general public, politicians andyes, often also among the medical and scientific community, butalso limited funding, dispersed research initiatives and seeminglyunrelated datasets usually make it more difficult to progress in theunderstanding of these disorders. Ectopic mineralization diseases,with pseudoxanthoma elasticum (PXE) as a paradigm disorder,have been no exception to the rule in facing all of these hurdles.But at the same time, PXE has been a prime example of the effortsto overcome these barriers. And to a certain point, they can beovercome as this Special Topic of Frontiers in Systems Biologyproves.Soft tissue mineralization is the result of a delicate interplayof a large number of protagonists—transcription factors, calci-fication promoting and inhibiting proteins and enzymes, home-ostatic cues (Schinke et al., 1999). It is precisely this complexitythat makes soft tissue calcification so difficult to comprehend. Atthe same time, it is the prototype of a pathophysiological mech-anism that cries out for a concerted action of different fields ofexpertise to build our insights into how it functions. Indeed, thereare many faces to soft tissue mineralization, several of which arecaptured in PXE. This rare autosomal recessive connective tis-sue disorder is characterized by ocular, skin, and cardiovascularsymptoms and can present important variability, particularly inthe severity of symptoms (Vanakker et al., 2008). The histologicalhallmark of PXE is mineralization and fragmentation of elasticfibers. PXE was shown to be caused by mutations in the ABCC6gene, encoding an ATP-dependent transporter protein, thoughthe physiological role and pathological consequences of ABCC6remain unclear (Le Saux et al., 2001).To achieve the ultimate goal of our research, a treatment tostabilize or cure PXE, there is a need to understand the functionof the ABCC6 protein which is perturbed in PXE. Despite theconsiderable progress made in the past years, which is reflectedon in this issue, many crucial questions remain unanswered.Concerted action also implies that we can look beyond our ownprotein of interest to other related proteins and diseases; theirstory—the difficulties as much as the successes—may give usvaluable insights in how we can proceed in understanding ourABC-transporter of interest.Next to mechanistic insights, the phenotype of patients shouldbe defined in the greatest detail. The importance of this for thefollow-up of patients goes without saying but cannot be seenindependently of our quest to understand the mechanisms of dis-ease. In this respect, recent findings on the unique characteristicsof the PXE vasculopathy and advances in the ophthalmologicalfeatures of PXE can give us important clues for the mechanismsthat lie beneath (De Zaeytijd et al., 2010; Lefthériotis et al., 2011;Campens et al., 2013).Finally, the molecular biology of these disorders needs befurther refined. More than a decade after the identification ofABCC6 as the causal gene for PXE, the molecular basis of PXEhas become increasingly more complex then was initially con-ceived. Not only have a number of genes been identified whichare associated with similar phenotypes, such as GGCX or ENPP1,but the variability of the PXE phenotype has also triggered thesearch for modifier genes (Vanakker et al., 2007; Nitschke et al.,2012). Though until now most of the secondary genes with alink to the phenotype should be considered susceptibility fac-tors in stead of true modifiers, prudent progress has been madethrough the characterization of the role of VEGF-A variants inocular neovascularization (Zarbock et al., 2009).The drive behind research endeavors aiming to understanda group of rare disorders is the result of the enthusiasm ofa group of dedicated scientists but—no less—also of patientsand their representing organizations. Despite the use of ani-mal models which can be very valuable for certain aspects ofdisease, the active involvement of patients in research, compris-ing clinical studies and experiments on tissues, remains invalu-able for the future of PXE research. The advocacy groups ofthese patients play an important role in translating researchfindings to the patients but have often also been a thrivingforce to gather and stimulate researchers and physicians aroundthe world.In this special topic of Frontiers in Systems Biology, someof the leading scientists and physicians in the field of PXE andectopic mineralization disorders have summarized the currentknowledge in their particular field of expertise and share theirthoughts on how further progress can bemade. Basic science con-tributions cover the complexity of ABCC6 transporter functionin (patho)physiological mineralization, the role of mesenchymalcells such as fibroblasts and mechanisms of remodeling in cal-cified vasculopathies. A perspective on the relevance of otherABC transporters for the study of ABCC6 and a methodologi-cal review on one of the innovative model organisms, the DanioRerio or zebrafish, provide a balance between current and futureendeavors. The molecular etiology is covered by reviews on thetranscriptional regulation of the ABCC6 gene and the role ofmodifier genes in PXE, while a contribution on ENPP1 and theoverlapping phenotype between PXE and Generalized ArterialCalcification of Infancy (GACI) makes the transition to clinicalpapers on specific aspects of the PXE retinopathy and vascu-lopathy. This research topic concludes with a perspective on thewww.frontiersin.org November 2013 | Volume 4 | Article 207 | 1Vanakker Coordinated orphan disease researchcurrent and future role of advocacy groups in orphan diseaseresearch.The rarity of hereditary soft tissue mineralization disordersrequire a coordinated effort at all levels mentioned above toobtain faster advances in knowledge of disease pathophysiol-ogy and its rapid translation into the clinic. This will inevitablyimprove health care for patients suffering from these orphan dis-eases, but may also lead to valuable insights on more commondisorders such as atherosclerosis and stroke as well as on the pro-cess of aging. Though maybe not always obvious at first sight,there is thus, unquestionably a relation with some of the globalhealth care problems the world is facing today and will continueto face in the future. This Special Topic evidences how the workof several research groups on rare mineralization diseases can bebrought together to reflect what is currently living in the field. Atthe same time, it should be an incentive to work further on a plat-form to integrate the research findings in these diseases retro- andprospectively. Only by uniting our attempts to gain insights in thecomplexity of soft tissue mineralization will we be able to get agrip on these diseases.REFERENCESCampens, L., Vanakker, O. M., Trachet, B., Segers, P., Leroy, B. P., De Zaeytijd,J., et al. (2013). Characterization of cardiovascular involvement in pseudox-anthoma elasticum families. Ather. Thromb. Vasc. Biol. 33, 2646–2652. doi:10.1161/ATVBAHA.113.301901De Zaeytijd, J., Vanakker, O. M., Coucke, P. J., De Paepe, A., De Laey, J. J, andLeroy, B. P. (2010). Added value of infrared, red-free and autofluorescence fun-cus imaging in pseudoxanthoma elasticum. Br. J. Ophthalmol. 94, 479–486. doi:10.1136/bjo.2009.162644Lefthériotis, G., Abraham, P., Le Corre, Y., Le Saux, O., Henrion, D., Ducluzeau,P. H., et al. (2011). Relationship between ankle brachial index and arterialremodeling in pseudoxanthoma elasticum. J. Vasc. Surg. 54, 1390–1394. doi:10.1016/j.jvs.2011.04.041Le Saux, O., Beck, K., Sachsinger, C., Silvestri, C., Treiber, C., Göring, H. H., et al.(2001). A spectrum of ABCC6 mutations is responsible for pseudoxanthomaelasticum. Am. J. Hum. Genet. 69, 749–764. doi: 10.1086/323704Nitschke, Y., Baujat, G., Botschen, U., Wittkampf, T., du Moulin, M., Stella, J., et al.(2012). Generalized arterial calcification of infancy and pseudoxanthoma elas-ticum can be caused by mutations in either ENPP1 or ABCC6. Am. J. Hum.Genet. 90, 25–39. doi: 10.1016/j.ajhg.2011.11.020Schinke, T., McKee, M. D., and Karsenty, G. (1999). Extracellular matrix calcifica-tion: where is the action? Nat. Genet. 21, 225–229.Vanakker, O.M., Leroy, B. P., Coucke, P., Bercovitch, L. G., Uitto, J., Viljoen, D., et al.(2008). Novel clinico-molecular insights in pseudoxanthoma elasticum pro-vide an efficient molecular screening method and a comprehensive diagnosticflowchart. Hum. Mut. 29:205. doi: 10.1002/humu.9514Vanakker, O. M., Martin, L., Gheduzzi, D., Leroy, B. P., Loeys, B. L.,Guerci, V. I., et al. (2007). Pseudoxanthoma elasticum-like phenotype withcutis laxa and multiple coagulation factor deficiency represents a sepa-rate genetic entity. J. Invest. Dermatol. 127, 581–587. doi: 10.1038/sj.jid.5700610Zarbock, R., Hendig, D., Szlsika, C., Kleesiek, K., and Gotting, C. (2009). Vascularendothelial growth facyor gene polymorphisms as prognostic markers forocular manifestations in pseudoxanthoma elasticum. Hum. Mol. Genet. 18,3344–3351. doi: 10.1093/hmg/ddp259Received: 24 September 2013; accepted: 27 September 2013; published online: 01November 2013.Citation: Vanakker OM (2013) Coordinated orphan disease research: yes, we can!Front. Genet. 4:207. doi: 10.3389/fgene.2013.00207This article was submitted to Systems Biology, a section of the journal Frontiers inGenetics.Copyright © 2013 Vanakker. This is an open-access article distributed under theterms of the Creative Commons Attribution License (CC BY). The use, distribution orreproduction in other forums is permitted, provided the original author(s) or licensorare credited and that the original publication in this journal is cited, in accordance withaccepted academic practice. No use, distribution or reproduction is permitted whichdoes not comply with these terms.Frontiers in Genetics | Systems Biology November 2013 | Volume 4 | Article 207 | 2

Coordinated orphan disease research : yes, we can!

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Coordinated orphan disease research : yes, we can!

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