14q32.12

ADCL2,ARCL1A,ARMD3,DANCE,EVEC,FIBL-5,HNARMD,UP50

Bladder cancer

The expression of Fibulin-5 is downregulated in human bladder carcinoma samples (Hu et al., 2011). Increased proliferation and invasiveness were observed in a bladder cancer cell line with overexpression of Fibulin-5 (Hu et al., 2011).

Breast cancer

The role of Fibulin-5 in breast cancer is still controversial. Oncomine database shows the reduction of Fibulin-5 mRNA in breast carcinomas, however, induction of Fibulin-5 expression is detected in breast cancer patient tissue by immunostaining (Lee et al., 2008). In addition, overexpression of Fibulin-5 can enhance tumor growth in an orthotopic mouse model of breast cancer (Lee et al., 2008). Meanwhile, overexpression of Fibulin-5 in breast cancer cells can reduce metastasis to liver and lung (Moller et al., 2011). The discrepancy between these studies could be due to cell line and mouse model differences. Fibulin-5 is also reported to participate in epithelial-mesenchymal-transition (EMT) in breast cancer cell lines in a MMP-dependent manner (Lee et al., 2008). However, the mechanism of Fibulin-5 regulation of MMP is unclear. For example, Fibulin-5 has been shown to inhibit and activate MMP9 activity, (Budatha et al., 2011; Lee et al., 2008; Moller et al., 2011).

Lung cancer

Fibulin-5 expression is silenced in multiple lung cancer cell lines and human lung cancer samples by hypermethylation of the promoter region (Yue et al., 2009). Overexpression of Fibulin-5 reduces lung cancer invasion and metastasis through suppression of the MMP-7 expression and ERK phosphorylation (Yue et al., 2009).

Ovarian cancer

The expression level of Fibulin-5 correlates inversely with the severity of disease (Wang et al., 2010). Expression of Fibulin-5 is also remarkably decreased in metastatic sites.

Pancreatic cancer

Fibulin-5 is required for aggressive tumor growth and angiogenesis in a mouse model of pancreatic cancer (Schluterman et al., 2010). Tumor weight and blood vessel density in Fbln5^-/- or Fbln5^RGE/RGE mice are significantly reduced compared with wildtype mice in subcutaneous and orthotopic models. Increased level of ROS, DNA damage and apoptotic endothelial cells were detected in tumors grown in Fibulin-5 deficient mice. In vitro analysis identified that Fibulin-5 reduces ROS production in a fibronectin and integrin β1-dependent manner (Schluterman et al., 2010).

Age-related macular degeneration (AMD)

DNA sequencing revealed 10 distinct heterozygous missense mutations in Fbln5 in 1-2% of AMD patients (Auer-Grumbach et al., 2011; Lotery et al., 2006; Stone et al., 2004). The underlying biochemical basis of two missense mutations, I169T and G267S was further studied by nuclear magnetic resonance (NMR) and chromophoric calcium chelation experiments. The results show that G267S substitution leads to protein misfolding and inhibition of secretion, but not the I169T substitution (Schneider et al., 2010).

Age-related macular degeneration (AMD) is an eye disease affecting the macula and is the main reason for irreversible version loss in elderly people (Lotery et al., 2006).

Charcot-Marie-Tooth disease (CMT)

Missense mutations of Fbln5 were detected in CMT neuropathy patients (Auer-Grumbach et al., 2011).

Charcot-Marie-Tooth disease (CMT) is an autosomal dominantly inherited disorder of peripheral nervous system (Auer-Grumbach et al., 2011). It is characterized by lifelong disabilities because of muscle weakness and loss of touch sensation (Auer-Grumbach et al., 2011).

Cutis laxa

Mutations in Fbln5 have been identified in hereditary and acquired forms of cutis laxa. Three homozygous mutations (C217R, S227P and R284X) in Fbln5 have been reported in autosomal recessive cutis laxa patients (Claus et al., 2008; Elahi et al., 2006; Loeys et al., 2002). In addition, a heterozygous in-frame tandem duplication of Fbln5 exon 5-8 has been discovered in a sporadic cutis laxa patient (Markova et al., 2003). Mutational analysis also shows that a cutis laxa patient has a heterozygous missense mutation (G202R) in Fbln5 and compound heterozygous mutation in elastin alleles (A55V and G773D) (Hu et al., 2006b). These findings further support that Fibulin-5 is essential for the formation and maturation of the tropoelastin self-aggregation process, which is required for elastic fiber assembly (Hu et al., 2006a).

Cutis laxa is a connective tissue disorder characterized by loose and redundant skin and multiple internal organ abnormalities due to fragmentation and paucity of elastic fibers.

Pelvic organ prolapse (POP)

Lower level expression of Fibulin-5 was identified in patients with POP (Soderberg et al., 2009; Takacs et al., 2009). It is reported that Fibulin-5 can prevent the development of POP by regulating elastic fiber homeostasis and inactivating MMP-9 in the vaginal wall (Budatha et al., 2011).

Pelvic organ prolapse (POP) is a common disease for elder women characterized by loss of pelvic floor support leading to protrusion of pelvic organs like uterus, bladder and vagina.

Thoracic aortic aneurysmal disease (TAD)

The expression of aortic Fibulin-5 is significantly decreased in patients with TAD. The low level of Fibulin-5 strongly correlates with disorganization of elastic fibers, which may contribute to aorta abnormality (Wang et al., 2005).

Thoracic aortic aneurysmal disease (TAD) is an aortic disorder characterized by loss of elastin in the wall of aorta (Wang et al., 2005).