Haploinsufficiency of elastin gene may lead to familial cardiopathy and pulmonary emphysema.
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ABSTRACT: Elastin is a major component of the mammalian lung, predominantly found in the alveoli. Destruction of alveolar elastic fibers is implicated in the pathogenic mechanism of emphysema in adults. These data define a role for elastin in the structure and function of the mature lung, and suggest that elastin is important for alveogenesis. To investigate the role of elastin in lung development, we examined mice lacking elastin (Eln-/-). At birth, the distal air sacs of Eln-/- lungs dilate to form abnormally large cavities. This phenotype appears before the synthesis and deposition of alveolar elastin, a process mediated by myofibroblasts and initiated after postnatal Day 4. Morphometric analyses demonstrate that the perinatal development of terminal airway branches is arrested in Eln-/- mice. The branching defect is accompanied by fewer distal air sacs that are dilated with attenuated tissue septae, a condition reminiscent of emphysema. Elastin expression in the lung parenchyma before alveogenesis is localized to the mesenchyme surrounding the developing airways, supporting a role for elastin in airway branching. Thus, in addition to its role in the structure and function of the mature lung, elastin is essential for pulmonary development and is important for terminal airway branching.American Journal of Respiratory Cell and Molecular Biology 10/2000; 23(3):320-6. · 4.11 Impact Factor
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ABSTRACT: Cutis laxa is an extremely rare disorder characterized by marked skin laxity. Few cases of cutis laxa have been described worldwide. Clinical presentation and mode of inheritance show considerable heterogeneity; autosomal dominant, autosomal recessive, and X-linked recessive forms have been reported. Only 3 mutations in the elastin gene have been described as the genetic cause of the autosomal dominant form of cutis laxa. A 45-year-old woman and her 19-year-old son presented with inelastic, loose-hanging, and wrinkled skin that appeared prematurely aged and were clinically diagnosed as having cutis laxa. Mutational analysis of the elastin gene evidenced a novel mutation (2292delC) that predicts a frameshift in the coding region and causes translation to proceed into the 3'-untranslated region. This would replace the C-terminal amino acid of the normal elastin protein with a novel sequence. This article is the fourth report of autosomal dominant cutis laxa to appear in the literature in which a mutation in the elastin gene has been correlated with the disease.Archives of Dermatology 10/2004; 140(9):1135-9. · 4.31 Impact Factor
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ABSTRACT: The destruction of elastic fibers has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Emphysema has been described in autosomal dominant cutis laxa, which can be caused by mutations in the elastin gene. Previously, a rare functional mutation in the terminal exon of elastin was found in a case of severe, early-onset COPD. To test the hypothesis that other similar elastin mutations may predispose to COPD, we screened 90 probands from the Boston Early-Onset COPD Study and 90 smoking control subjects from the Normative Aging Study for mutations in elastin exons using high-resolution DNA melt analysis followed by resequencing. Rare nonsynonymous single-nucleotide polymorphisms (SNPs) seen only in cases were examined for segregation with airflow obstruction within pedigrees. Common nonsynonymous SNPs were tested for association with COPD in a family-based analysis of 949 subjects from the Boston Early-Onset COPD Study, and in a case-control analysis in 389 COPD cases from the National Emphysema Treatment Trial and 472 control subjects from the Normative Aging Study. Of 28 elastin variants found, 3 were nonsynonymous SNPs found only in cases. The previously described Gly773Asp mutation was found in another proband. The other two SNPs did not clearly segregate with COPD within families. Two common nonsynonymous SNPs did not demonstrate significant associations in either a family-based or case-control analysis. Exonic SNPs in the elastin gene do not appear to be common risk factors for severe COPD.American Journal of Respiratory Cell and Molecular Biology 12/2008; 40(6):751-5. · 4.15 Impact Factor
Haploinsufficiency of Elastin Gene May Lead to
Familial Cardiopathy and Pulmonary Emphysema
Jacoba J Louw,1,2* Geert Verleden,3Marc Gewillig,1and Koenraad Devriendt2
1Department of Congenital and Pediatric Cardiology, University Hospitals Leuven, Belgium
2Centre for Human Genetics, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium
3Lung Transplantation Unit, University Hospitals Leuven, Belgium
Manuscript Received: 9 June 2011; Manuscript Accepted: 16 April 2012
TO THE EDITOR:
Wan et al.  reported in this journal a non-smoking adult
person with Williams–Beuren syndrome and emphysema, and
raised the question if defects in the elastin gene are associated
with increased susceptibility toward developing chronic obstruc-
tive pulmonary disease (COPD) and emphysema. Additional sup-
with early onset COPD [Kelleher et al., 2005; Cho et al., 2009], as
wellas the fact that changes in the elastingenearealso described in
cases of autosomal dominant form of cutis laxa (OMIM 123700)
alveolar growth [Wendel et al., 2000; Shifren et al., 2006]. Mice
ing patterns. An increased inflammatory response to cigarette
positive, mouse ELN gene null) animals, with about one third of
normal elastin expression levels and significantly decreased colla-
gen levels, showed grossly abnormal pulmonary structure with
severe congenital emphysema that is present from birth but not
progressive. Finally, mice deficient in elastin (ELN?/?) exhibit
abnormalities in the lungs that are morphologically similar to
emphysema [Shifren et al., 2006].
with both cardiac and pulmonary manifestations, i.e., peripheral
pulmonary emphysema. The family is Caucasian and the parents
The index patient, a boy, was referred shortly after birth to our
Tertiary Pediatric Cardiology Unit after a cardiac murmur was
heard at the first clinical examination. The diagnosis of an impor-
pulmonary arteries. This initially led to mild right ventricular
hypertrophy, which subsequently regressed with sufficient growth
of the pulmonary arteries. A notch in the ascending aorta was also
present on echocardiography, but without a pressure gradient and
only a minimal degree of aortic insufficiency, thus posing no
subsequent left ventricular hypertrophy, by the age of 2 years
surgical correction was necessary with angioplasty.
The father of our patient is known to have supra-aortic stenosis
underwent bilateral lung transplantation due to pulmonary
years. Alpha 1-antitrypsin deficiency (A1AT) was excluded; 2.03g/L
in serum as well as absence of the following recurrent mutations:
p.E342K (Z-variant) in exon 5 and p.E264V (S-variant) in exon 3.
Furthermore, the paternal grandfather died at the age of 45 years
due to pulmonary emphysema. He was also a smoker and was
known to have a cardiopathy, although more specific detail is not
Neither our index patient, nor his father had any dysmorphic
features, as determined by an experienced clinical geneticist. The
father of our patient and his grandfather have no siblings, but have
the same phenotype, i.e., cardiopathy and a history of pulmonary
Jacoba J Louw, M.D., UZ Leuven - Pediatric Cardiology, Herestraat 49
Leuven 3000, Belgium. E-mail: firstname.lastname@example.org
Article first published online in Wiley Online Library
(wileyonlinelibrary.com): 00 Month 2012
How to Cite this Article:
Louw JJ, Verleden G, Gewillig M, Devriendt
K. 2012. Haploinsufficiency of elastin gene
may lead to familial cardiopathy and
Am J Med Genet Part A.
? 2012 Wiley Periodicals, Inc.
emphysema presenting at a young age. There were no reported
phenotypes in the rest of the family.
Due to the paternally known cardiopathy, the suspicion of a
haplosufficiency in the elastin genewith dominantinheritance was
an ELN probe did not show a deletion in this gene, but a hetero-
zygous ELN point mutation was found in both the father and our
a change in the start codon methionine, and due to the fact that no
other in-frame methionine is present in the elastin mRNA, this
mutation is predicted to lead to the absence of the elastin protein.
This mutation has not been reported before, and is not a known
polymorphism or rare variant.
mutation in this elastin gene might be responsible for an earlier or
more severe presentation of pulmonary emphysema. Additional
susceptible to emphysema. Additional known emphysema risk
factors, i.e., a carrier status for A1AT deficiency could also have
aneffect butwereexcluded in the father. Our index patient andhis
thus too young to correctly perform pulmonary function testing.
Considering that he currently has no respiratory symptoms, we
chose not to perform a CT scan, as this will not have any clinical
implications. Furthermore, his father only presented with respira-
tory symptoms in the third decade.
This family size is too small to be able to make a conclusion of
segregation with disease. Only two affected individuals are alive,
andboth carrytheelastinmutation.The grandmotheroftheindex
was not available for testing, and the mother and siblings of our
phenotype and a normal cardiac echocardiography.
secondary smoking. In a more general way, this observation lends
further support to the notion that haploinsufficiency for ELN is a
risk factor for emphysema.
early-onset chronic obstructive pulmonary disease. Cell Mol Biol 40:
Kelleher CM, Silverman EK, Broekelmann T, Litonjua AA, Hernandez M,
Cell Mol Biol 33:355–362.Epub 2005 Aug 4.
Rodriguez-RevengaL,IranzoP,BadenasC,PuigS,Carri? oA,Mil? aM.2004.
A novel elastin gene mutation resulting in an autosomal dominant form
of cutis laxa. Arch Dermatol 140:1135–1139.
Mecham Robert P. 2006. Elastin protein levels are a vital modifier
affecting normal lung development and susceptibility to emphysema.
Am J Physiol Lung Cell Mol Physiol 292:L778–L787.
with severe lung disease: Synthesis and matrix deposition of mutant
tropoelastin. J Invest Dermatol 124:1193–1199.
distal airway development in mice lacking elastin. Am J Respir Cell Mol
function and emphysema in Williams-Beuren syndrome. Am J Med
Genet Part A 152A:653–656.
2 AMERICAN JOURNAL OF MEDICAL GENETICS PART A