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Open Access 01-12-2012 | Research

Characterization of a distinct lethal arteriopathy syndrome in twenty-two infants associated with an identical, novel mutation in FBLN4 gene, confirms fibulin-4 as a critical determinant of human vascular elastogenesis

Authors: Mahesh Kappanayil, Sheela Nampoothiri, Rajesh Kannan, Marjolijn Renard, Paul Coucke, Fransiska Malfait, Swapna Menon, Hiran K Ravindran, Renu Kurup, Muhammad Faiyaz-Ul-Haque, Krishna Kumar, Anne De Paepe

Published in: Orphanet Journal of Rare Diseases | Issue 1/2012

Abstract

Background

Vascular elasticity is crucial for maintaining hemodynamics. Molecular mechanisms involved in human elastogenesis are incompletely understood. We describe a syndrome of lethal arteriopathy associated with a novel,identical mutation in the fibulin 4 gene (FBLN4) in a unique cohort of infants from South India.

Methods

Clinical characteristics, cardiovascular findings, outcomes and molecular genetics of twenty-two infants from a distinct population subgroup,presenting with characteristic arterial dilatation and tortuosity during the period August 2004 to June 2011 were studied.

Results

Patients (11 males, 11 females) presented at median age of 1.5 months,belonging to unrelated families from identical ethno-geographical background; eight had a history of consanguinity. Cardiovascular features included aneurysmal dilatation, elongation, tortuosity and narrowing of the aorta, pulmonary artery and their branches. The phenotype included a variable combination of cutis laxa (52%), long philtrum-thin vermillion (90%), micrognathia (43%), hypertelorism (57%), prominent eyes (43%),sagging cheeks (43%), long slender digits (48%), and visible arterial pulsations (38%). Genetic studies revealed an identical c.608A > C (p. Asp203Ala) mutation in exon 7 of the FBLN4 gene in all 22 patients, homozygous in 21, and compound heterozygous in one patient with a p. Arg227Cys mutation in the same conserved cbEGF sequence.Homozygosity was lethal (17/21 died, median age 4 months). Isthmic hypoplasia (n = 9) correlated with early death (≤4 months).

Conclusions

A lethal, genetic disorder characterized by severe deformation of elastic arteries, was linked to novel mutations in the FBLN4 gene. While describing a hitherto unreported syndrome in this population subgroup, this study emphasizes the critical role of fibulin-4 in human elastogenesis.

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Coucke PJ, Willaert A, Wessels MW, Callewaert B, Zoppi N, De Backer J, Fox JE, Mancini GM, Kambouris M, Gardella R, Facchetti F, Willems PJ, Forsyth R, Dietz HC, Barlati S, Colombi M, Loeys B, De Paepe A: Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome. Nat Genet. 2006, 38 (4): 452-457. 10.1038/ng1764.CrossRefPubMed

Loeys BL, Chen J, Neptune ER, Judge DP, Podowski M, Holm T, Meyers J, Leitch CC, Katsanis N, Sharifi N: Xu Fl, Myers LA, Spevak PJ, Cameron DE, De Backer J, Hellemans J, Chen Y,Davis EC, Webb CL, Kress W, Coucke P, Rifkin DB, De Paepe AM, Dietz HC. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005, 37 (3): 275-281. 10.1038/ng1511.CrossRefPubMed

Pletcher BA, Fox JE, Boxer RA, Singh S, Blumenthal D, Cohen T, Brunson S, Tafreshi P, Kahn E: Four sibs with arterial tortuosity: description and review of the literature. Am J Med Genet. 1996, 66 (2): 121-128. 10.1002/(SICI)1096-8628(19961211)66:2<121::AID-AJMG1>3.0.CO;2-U.CrossRefPubMed

Al Fadley F, Al Manea W, Nykanen DG, Al Fadley A, Bulbul Z, Al Halees Z: Severe tortuosity and stenosis of the systemic, pulmonary and coronary vessels in 12 patients with similar phenotypic features: a new syndrome?. Cardiol Young. 2000, 10 (6): 582-589.CrossRefPubMed

Wessels MW, Catsman-Berrevoets CE, Mancini GM, Breuning MH, Hoogeboom JJ, Stroink H, Frohn-Mulder I, Coucke PJ, Paepe AD, Niermeijer MF, Willems PJ: Three new families with arterial tortuosity syndrome. Am J Med Genet A. 2004, 131 (2): 134-143.CrossRefPubMed

Loeys BL, Schwarze U, Holm T, Callewaert BL, Thomas GH, Pannu H, De Backer JF, Oswald GL, Symoens S, Manouvrier S, Roberts AE, Faravelli F, Greco MA, Pyeritz RE, Milewicz DM, Coucke PJ, Cameron DE, Braverman AC, Byers PH, De Paepe AM, Dietz HC: Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006, 355 (8): 788-798. 10.1056/NEJMoa055695.CrossRefPubMed

Callewaert BL, Willaert A, Kerstjens-Frederikse WS, De Backer J, Devriendt K, Albrecht B, Ramos-Arroyo MA, Doco-Fenzy M, Hennekam RC, Pyeritz RE, Krogmann ON, Gillessen-kaesbach G, Wakeling EL, Nik-zainal S, Francannet C, Mauran P, Booth C, Barrow M, Dekens R, Loeys BL, Coucke PJ, De Paepe AM: Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families. Hum Mutat. 2008, 29 (1): 150-158. 10.1002/humu.20623.CrossRefPubMed

Loeys B, Van Maldergem L, Mortier G, Coucke P, Gerniers S, Naeyaert JM, De Paepe A: Homozygosity for a missense mutation in fibulin-5 (FBLN5) results in a severe form of cutis laxa. Hum Mol Genet. 2002, 11 (18): 2113-2118. 10.1093/hmg/11.18.2113.CrossRefPubMed

Hucthagowder V, Sausgruber N, Kim KH, Angle B, Marmorstein LY, Urban Z: Fibulin-4: a novel gene for an autosomal recessive cutis laxa syndrome. Am J Hum Genet. 2006, 78 (6): 1075-1080. 10.1086/504304.PubMedCentralCrossRefPubMed

10.

Abdul Wahab A, Janahi IA, Eltohami A, Zeid A, Ul Haque MF, Teebi AS: A new type of Ehlers-Danlos syndrome associated with tortuous systemic arteries in a large kindred from Qatar. Acta Paediatr. 2003, 92 (4): 456-462.CrossRefPubMed

11.

Beuren AJ, Hort W, Kalbfleisch H, Müller H, Stoermer J: Dysplasia of the systemic and pulmonary arterial system with tortuosity and lengthening of the arteries. A new entity, diagnosed during life, and leading to coronary death in early childhood. Circulation. 1969, 39 (1): 109-115. 10.1161/01.CIR.39.1.109.CrossRefPubMed

12.

Ertugrul A: Diffuse tortuosity and lengthening of the arteries. Circulation. 1967, 36 (3): 400-407. 10.1161/01.CIR.36.3.400.CrossRefPubMed

13.

Franceschini P, Guala A, Licata D, Di Cara G, Franceschini D: Arterial tortuosity syndrome. Am J Med Genet. 2000, 91 (2): 141-143. 10.1002/(SICI)1096-8628(20000313)91:2<141::AID-AJMG13>3.0.CO;2-6.CrossRefPubMed

14.

Gardella R, Zoppi N, Assanelli D, Muiesan ML, Barlati S, Colombi M: Exclusion of candidate genes in a family with arterial tortuosity syndrome. Am J Med Genet A. 2004, 126A (3): 221-228. 10.1002/ajmg.a.20589.CrossRefPubMed

15.

Meyer S, Faiyaz-Ul-Haque M, Zankl M, Sailer NL, Marx N, Limbach HG, Lindinger A: Arterial tortuosity syndrome. Klin Padiatr. 2005, 217 (1): 36-40. 10.1055/s-2004-822635.CrossRefPubMed

16.

Zaidi SHE, Peltekova V, Meyer S, Lindinger A, Paterson AD, Tsui LC, Faiyaz-Ul-Haque M, Teebi AS: A family exhibiting arterial tortuosity syndrome displays homozygosity for markers in the arterial tortuosity locus at chromosome 20q13. Clin Genet. 2005, 67 (2): 183-188.CrossRefPubMed

17.

Wagenseil JE, Mecham RP: New insights into elastic fiber assembly. Birth Defects Res C Embryo Today. 2007, 81 (4): 229-240. 10.1002/bdrc.20111.CrossRefPubMed

18.

Mithieux SM, Weiss AS: Elastin. Adv Protein Chem. 2005, 70: 437-461.CrossRefPubMed

19.

Royce PM, Steinmann BU: Connective tissue and its heritable disorders. John Wiley and Sons. 2002, 1201:

20.

Chen Q, Zhang T, Roshetsky JF, Ouyang Z, Essers J, Fan C, Wang Q, Hinek A, Plow EF, Dicorleto PE: Fibulin-4 regulates expression of the tropoelastin gene and consequent elastic-fibre formation by human fibroblasts. Biochem J. 2009, 423 (1): 79-89. 10.1042/BJ20090993.PubMedCentralCrossRefPubMed

21.

Choudhary R, McGovern A, Ridley C, Cain SA, Baldwin A, Wang MC, Guo C, Mironov A Jr, Drymoussi Z, Trump D, Shuttleworth A, Baldock C, Kielty CM: Differential regulation of elastic fiber formation by fibulins-4 and-5. J Biochem. 2009, 284 (36): 24553-24567.

22.

Hanada K, Vermeij M, Garinis GA, de Waard MC, Kunen MG, Myers L, Maas A, Duncker DJ, Meijers C, Dietz HC, Kanaar R, Essers J: Perturbations of vascular homeostasis and aortic valve abnormalities in fibulin-4 deficient mice. Circ Res. 2007, 100 (5): 738-746. 10.1161/01.RES.0000260181.19449.95.CrossRefPubMed

23.

Satish G, Nampoothiri S, Kappanayil M: Images in cardiovascular medicine. Arterial tortuosity syndrome: phenotypic features and cardiovascular manifestations. Circulation. 2008, 117 (23): e477-e478.PubMed

24.

Timpl R, Sasaki T, Kostka G, Chu ML: Fibulins: a versatile family of extracellular matrix proteins. Nat Rev Mol Cell Biol. 2003, 4 (6): 479-489. 10.1038/nrm1130.CrossRefPubMed

25.

Argraves WS, Greene LM, Cooley MA, Gallagher WM: Fibulins: physiological and disease perspectives. EMBO Rep. 2003, 4 (12): 1127-1131. 10.1038/sj.embor.7400033.PubMedCentralCrossRefPubMed

26.

Kobayashi N, Kostka G, Garbe JH, Keene DR, Bächinger HP, Hanisch FG, Markova D, Tsuda T, Timpl R, Chu ML, Sasaki T: A comparative analysis of the fibulin protein family. Biochemical characterization, binding interactions, and tissue localization. J Biol Chem. 2007, 282 (16): 11805-11816.CrossRefPubMed

27.

McLaughlin PJ, Chen Q, Horiguchi M, Starcher BC, Stanton JB, Broekelmann TJ, Marmorstein AD, McKay B, Mecham R, Nakamura T, Marmorstein LY: Targeted disruption of fibulin-4 abolishes elastogenesis and causes perinatal lethality in mice. Mol Cell Biol. 2006, 26 (5): 1700-1709. 10.1128/MCB.26.5.1700-1709.2006.PubMedCentralCrossRefPubMed

28.

Nakamura T, Lozano PR, Ikeda Y, Iwanaga Y, Hinek A, Minamisawa S, Cheng CF, Kobuke K, Dalton N, Takada Y, Tashiro K, Ross J Jr, Honjo T, Chien KR: Fibulin-5/DANCE is essential for elastogenesis in vivo. Nature. 2002, 415 (6868): 171-10.1038/415171a.CrossRefPubMed

29.

Dasouki M, Markova D, Garola R, Sasaki T, Charbonneau NL, Sakai LY, Chu ML: Compound heterozygous mutations in fibulin-4 causing neonatal lethal pulmonary artery occlusion, aortic aneurysm, arachnodactyly, and mild cutis laxa. Am J Med Genet A. 2007, 143A (22): 2635-2641. 10.1002/ajmg.a.31980.CrossRefPubMed

30.

Hoyer J, Kraus C, Hammersen G, Geppert JP, Rauch A: Lethal cutis laxa with contractural arachnodactyly, overgrowth and soft tissue bleeding due to a novel homozygous fibulin-4 gene mutation. Clin Genet. 2009, 76 (3): 276-281. 10.1111/j.1399-0004.2009.01204.x.CrossRefPubMed

31.

Renard M, Holm T, Veith R, Vallewaert BL, Ades LC, Baspinar O, Pickart A, Dasouki M, Hoyer J, Rauch A, Trapane P, Earing MG, Coucke PJ, Sakai LY, Dietz HC, De Paepe AM, Loeys BL: Altered TGFbeta signaling and cardiovascular manifestations in patients with autosomal recessive cutis laxa type I caused by fibulin-4 deficiency. Eur J Hum Genet. 2010, 18 (8): 895-901. 10.1038/ejhg.2010.45.PubMedCentralCrossRefPubMed

32.

Huang J, Davis EC, Chapman SL, Budatha M, Marmorstein LY, Word RA, Yanagisawa H: Fibulin-4 deficiency results in ascending aortic aneurysms: a potential link between abnormal smooth muscle cell phenotype and aneurysm progression. Circ Res. 2010, 106 (3): 583-592. 10.1161/CIRCRESAHA.109.207852.PubMedCentralCrossRefPubMed

33.

Government of India, Ministry of Home Affairs:[http://www.censusindia.gov.in/] ,

34.

Genesis and growth of the Mappila community:[http://www.jaihoon.com] ,

35.

Ross R, Bornstein P: The elastic fiber. I. The separation and partial characterization of its macromolecular components. J Cell Biol. 1969, 40 (2): 366-381.PubMed

36.

Warren AE, Boyd ML, O'Connell C, Dodds L: Dilatation of the ascending aorta in paediatric patients with bicuspid aortic valve: frequency, rate of progression and risk factors. Heart. 2006, 92 (10): 1496-1500. 10.1136/hrt.2005.081539.PubMedCentralCrossRefPubMed

37.

Pettersen MD, Du W, Skeens ME, Humes RA: Regression equations for calculation of z scores of cardiac structures in a large cohort of healthy infants, children, and adolescents: an echocardiographic study. J Am Soc Echocardiogr. 2008, 21 (8): 922-934. 10.1016/j.echo.2008.02.006.CrossRefPubMed

38.

Pediatric and Fetal Echo Z-Score Calculators:[http://parameterz.blogspot.com,

Title: Characterization of a distinct lethal arteriopathy syndrome in twenty-two infants associated with an identical, novel mutation in FBLN4 gene, confirms fibulin-4 as a critical determinant of human vascular elastogenesis
Authors: Mahesh Kappanayil
Sheela Nampoothiri
Rajesh Kannan
Marjolijn Renard
Paul Coucke
Fransiska Malfait
Swapna Menon
Hiran K Ravindran
Renu Kurup
Muhammad Faiyaz-Ul-Haque
Krishna Kumar
Anne De Paepe
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: Orphanet Journal of Rare Diseases / Issue 1/2012
Electronic ISSN: 1750-1172
DOI: https://doi.org/10.1186/1750-1172-7-61

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Characterization of a distinct lethal arteriopathy syndrome in twenty-two infants associated with an identical, novel mutation in FBLN4 gene, confirms fibulin-4 as a critical determinant of human vascular elastogenesis

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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