Comprehensive Clinical and Molecular Analysis of 12 Families with Type 1 Recessive Cutis Laxa

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 2 probands, whereas 9 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. Gastro-intestinal 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) signaling. 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 signaling. We conclude that LTBP4 mutations cause disease through both loss of function and gain of function mechanisms.

Novel FBLN5 Mutation of Congenital Autosomal Recessive Cutis Laxa With Isolated Right Ventricular Non-Compaction (RVNC): New Findings on Echocardiographic Speckle-Tracking Strain Imaging of RVNC

“…Callewaert et al and other investigators have reported pulmonary emphysema and vascular complications as two main characteristics of ARCL type I (10,11). However, our case with the novel homozygous mutation has limited segments, with pulmonary emphysema and no vascular involvement.…”

A large lung gene expression study identifying fibulin-5 as a novel player in tissue repair in COPD

“…FBLN5 knockout mice survive to adulthood but develop pronounced elastinopathy with human aging phenotypes like loose skin, vascular abnormalities, severe emphysema and genital prolapse 15 16. This phenotype in mice is very similar to the human connective tissue disorder cutis laxa, which can be caused by mutations in FBLN5 and is often associated with severe emphysema 19. Based on these findings we consider FBLN5 as a potential novel player in tissue repair in COPD and decided to further focus on this gene.…”

Severe congenital cutis laxa with cardiovascular manifestations due to homozygous deletions in ALDH18A1

“…In two patients with ALDH18A1-related CL, kinky tortuosity of brain vessels was reported [16,17] demonstrating that in this severe form of CL vessels are especially vulnerable. Therefore, vessels should not only be assessed in ADCL, ARCL1, and ATS that are well known for their arterial malformations [1,18,19], but also in proline biosynthesis pathologies.…”