Article

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: 10.99). 05/2003; 72(4):998-1004. DOI: 10.1086/373940
Source: PubMed

ABSTRACT 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, Jul 29, 2015
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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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    Brain 06/2011; 134(Pt 6):1839-52. DOI:10.1093/brain/awr076 · 10.23 Impact Factor
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    • "Molecular heterogeneity has been suggested in ADCL (Graul-Neumann, et al., 2008; Markova, et al., 2003). Our data now suggest that, at least in the majority of cases, ADCL can be attributed to a mutant TE in which the C-terminus is replaced by an extended missense peptide sequence as a result of a frameshift (fmTE). "
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