Article

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

Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Filadelfia, Pennsylvania, United States
The American Journal of Human Genetics (Impact Factor: 10.93). 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
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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.
    Full-text · Article · Feb 2013 · Orphanet Journal of Rare Diseases
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    • "Before this study was published, mutations in FBLN5 were associated only with the connective tissue disorder cutis laxa (Loeys et al., 2002; Markova et al., 2003; Lotery et al., 2006; Nascimento et al., 2010) and age-related macular degeneration leading to vision loss in those aged 450 years (Stone et al., 2004; Lotery et al., 2006). Auer-Grumbach et al. (2011) were the first to describe a large family with demyelinating Charcot– Marie–Tooth (CMT1) and linkage with the interval on chromosome 14. "

    Full-text · Article · Jan 2013 · Brain
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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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    ABSTRACT: Autosomal recessive cutis laxa type I (ARCL type I) is characterized by generalized cutis laxa with pulmonary emphysema and/or vascular complications. Rarely, mutations can be identified in FBLN4 or FBLN5. Recently, LTBP4 mutations have been implicated in a similar phenotype. Studying FBLN4, FBLN5, and LTBP4 in 12 families with ARCL type I, we found bi-allelic FBLN5 mutations in two probands, whereas nine probands harbored biallelic mutations in LTBP4. FBLN5 and LTBP4 mutations cause a very similar phenotype associated with severe pulmonary emphysema, in the absence of vascular tortuosity or aneurysms. Gastrointestinal and genitourinary tract involvement seems to be more severe in patients with LTBP4 mutations. Functional studies showed that most premature termination mutations in LTBP4 result in severely reduced mRNA and protein levels. This correlated with increased transforming growth factor-beta (TGFβ) activity. However, one mutation, c.4127dupC, escaped nonsense-mediated decay. The corresponding mutant protein (p.Arg1377Alafs(*) 27) showed reduced colocalization with fibronectin, leading to an abnormal morphology of microfibrils in fibroblast cultures, while retaining normal TGFβ activity. We conclude that LTBP4 mutations cause disease through both loss of function and gain of function mechanisms.
    Full-text · Article · Jan 2013 · Human Mutation
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