Genetic Heterogeneity of Cutis Laxa: A Heterozygous Tandem Duplication within the Fibulin-5 (FBLN5) Gene

Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 05/2003; 72(4):998-1004. DOI: 10.1086/373940
Source: PubMed


Inherited cutis laxa is a connective tissue disorder characterized by loose skin and variable internal organ involvement, resulting from paucity of elastic fibers. Elsewhere, frameshift mutations in the elastin gene have been reported in three families with autosomal dominant inheritance, and a family with autosomal recessive cutis laxa was recently reported to have a homozygous missense mutation in the fibulin-5 gene. In the present study, we analyzed the gene expression of elastin and fibulins 1-5 in fibroblasts from five patients with cutis laxa. One patient was found to express both normal (2.2 kb) and mutant (2.7 kb) fibulin-5 mRNA transcripts. The larger transcript contains an internal duplication of 483 nucleotides, which resulted in the synthesis and secretion of a mutant fibulin-5 protein with four additional tandem calcium-binding epidermal growth factor-like motifs. The mutation arose from a 22-kb tandem gene duplication, encompassing the sequence from intron 4 to exon 9. No fibulin-5 or elastin mutations were detected in the other patients. The results demonstrate that a heterozygous mutation in fibulin-5 can cause cutis laxa and also suggest that fibulin-5 and elastin gene mutations are not the exclusive cause of the disease.

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Available from: Dessislava Markova,
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    • "Two reports indicated molecular heterogeneity in ADCL. In a single ADCL patient, a tandem duplication in the FBLN5 gene was shown to result in secretion of mutant protein, suggesting a dominant negative effect [11]. However, mutant protein integration in the extracellular matrix has been shown in FBLN5 related ARCL type 1 [31] and carriers of these mutations do not have a cutis laxa phenotype. "
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    ABSTRACT: BACKGROUND: Elastin gene mutations have been associated with a variety of phenotypes. Autosomal dominant cutis laxa (ADCL) is a rare disorder that presents with lax skin, typical facial characteristics, inguinal hernias, aortic root dilatation and pulmonary emphysema. In most patients, frameshift mutations are found in the 3' region of the elastin gene (exons 30-34) which result in a C-terminally extended protein, though exceptions have been reported. METHODS: We clinically and molecularly characterized the thus far largest cohort of ADCL patients, consisting of 19 patients from six families and one sporadic patient. RESULTS: Molecular analysis showed C-terminal frameshift mutations in exon 30, 32, and 34 of the elastin gene and identified a mutational hotspot in exon 32 (c.2262delA). This cohort confirms the previously reported clinical constellation of skin laxity (100%), inguinal hernias (51%), aortic root dilatation (55%) and emphysema (37%). CONCLUSION: ADCL is a clinically and molecularly homogeneous disorder, but intra- and interfamilial variability in the severity of organ involvement needs to be taken into account. Regular cardiovascular and pulmonary evaluations are imperative in the clinical follow-up of these patients.
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    • "Heterozygous mutations in both the elastin (ELN; MIM# 130160) and fibulin 5 (FBLN5; MIM# 604580) genes have been reported in ADCL [Callewaert et al., 2011; Markova et al., 2003; Szabo et al., 2006; Tassabehji et al., 1998; Urban et al., 2005]. Autosomal recessive cutis laxa (ARCL) comprises several subtypes. "
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    • "It is critical for correct deposition of elastin, mediates cell-matrix communication and regulates organogenesis, fibrogenesis, vascular remodelling and tumour metastasis (Zheng et al., 2007; Yanagisawa et al., 2009). Three homozygous missense mutations (p.C217R, p.S227P and p.R284X) in FBLN5 have been reported in patients with an autosomal recessive, generalized form of the connective tissue disorder cutis laxa (Loeys et al., 2002; Elahi et al., 2006; Hu et al., 2006; Claus et al., 2008; Nascimento et al., 2010), and a heterozygous in-frame tandem duplication of exons 5– 8 in FBLN5 was seen in a sporadic patient with cutis laxa suggesting that the large protein acts in a dominant negative way (Markova et al., 2003). Ten distinct, heterozygous FBLN5 missense mutations have been associated with age-related macular degeneration, the leading cause of severe visual loss among patients older than 50 years in the western world (Stone et al., 2004; Lotery et al., 2006; Jones et al., 2009, 2010; Schneider et al., 2010). "
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