Diagnostic Exome Sequencing Identifies a Novel Gene,<i>EMILIN1</i>, Associated with Autosomal‐Dominant Hereditary Connective Tissue Disease

Capuano, Alessandra; Bucciotti, Francesco; Farwell, Kelly D.; Davis, Brigette Tippin; Mroske, Cameron; Hulick, Peter J.; Weissman, Scott M.; Gao, Qingshen; Spessotto, Paola; Colombatti, Alfonso; Doliana, Roberto

doi:10.1002/humu.22920

Cited by 41 publications

(22 citation statements)

References 61 publications

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“…Emilin1 knockout mice showed defects of elastic fibers in aorta and skin suggesting that Emilin1 is implicated in elastogenesis and maintenance of blood vascular cell morphology [41]. The identification of a heterozygous missense variant in EMILIN1 in a proband with a connective disorder suggested this gene as a new disease gene for an autosomaldominant connective tissue disorder [42]. To our knowledge, a mouse model for Minar1 (alternative names KIAA1024 and UBTOR) does not yet exist.…”

Section: Plos Geneticsmentioning

confidence: 99%

A homozygous missense variant in CACNB4 encoding the auxiliary calcium channel beta4 subunit causes a severe neurodevelopmental disorder and impairs channel and non-channel functions

et al. 2020

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P/Q-type channels are the principal presynaptic calcium channels in brain functioning in neurotransmitter release. They are composed of the pore-forming Ca V 2.1 α 1 subunit and the auxiliary α2δ-2 and β 4 subunits. β 4 is encoded by CACNB4, and its multiple splice variants serve isoform-specific functions as channel subunits and transcriptional regulators in the nucleus. In two siblings with intellectual disability, psychomotor retardation, blindness, epilepsy, movement disorder and cerebellar atrophy we identified rare homozygous variants in the genes LTBP1, EMILIN1, CACNB4, MINAR1, DHX38 and MYO15 by whole-exome sequencing. In silico tools, animal model, clinical, and genetic data suggest the p.(Leu126-Pro) CACNB4 variant to be likely pathogenic. To investigate the functional consequences of the CACNB4 variant, we introduced the corresponding mutation L125P into rat β 4b cDNA. Heterologously expressed wild-type β 4b associated with GFP-Ca V 1.2 and accumulated in presynaptic boutons of cultured hippocampal neurons. In contrast, the β 4b-L125P mutant failed to incorporate into calcium channel complexes and to cluster presynaptically. When co-expressed with Ca V 2.1 in tsA201 cells, β 4b and β 4b-L125P augmented the calcium current amplitudes, however, β 4b-L125P failed to stably complex with α 1 subunits. These results indicate that p.Leu125Pro disrupts the stable association of β 4b with native calcium channel complexes, whereas membrane incorporation, modulation of current density and activation properties of heterologously expressed channels remained intact. Wildtype β 4b was specifically targeted to the nuclei of quiescent excitatory cells. Importantly, the p.Leu125Pro mutation abolished nuclear targeting of β 4b in cultured myotubes and hippocampal neurons. While binding of β 4b to the known interaction partner PPP2R5D (B56δ) was not affected by the mutation, complex formation between β 4b-L125P and the neuronal TRAF2 and NCK

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Section: Plos Geneticsmentioning

confidence: 99%

A homozygous missense variant in CACNB4 encoding the auxiliary calcium channel beta4 subunit causes a severe neurodevelopmental disorder and impairs channel and non-channel functions

et al. 2020

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“…Loss of function in MFAP5 disrupts one of the microfibril associated proteins, MAGP-2. 46 Mutations in another microfibil associated protein, emilin1, have been recently reported to predispose to thoracic aortic aneurysm but additional families with TAAD due to mutations in EMILIN1 need to be identified to confirm this finding 47 . Mutations in the gene for elastin itself ( ELN ) cause dominant cutis laxa, and there are reports of these patients developing thoracic aortic aneurysms.…”

Section: Mutations In Elastin and Components Of The Microfibrilsmentioning

confidence: 99%

Structure of the Elastin-Contractile Units in the Thoracic Aorta and How Genes That Cause Thoracic Aortic Aneurysms and Dissections Disrupt This Structure

Karimi

Milewicz

2016

Canadian Journal of Cardiology

130

109

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The medial layer of the aorta confers elasticity and strength to the aortic wall and is composed of alternating layers of smooth muscle cells (SMCs) and elastic fibers. The SMC elastin-contractile unit is a structural unit that links the elastin fibers to the SMCs and is characterized by the following: 1. Layers of elastin fibers that are surrounded by microfibrils. 2. Microfibrils that bind to the integrin receptors in focal adhesions on the cell surface of the SMCs. 3. SMC contractile filaments that are linked to the focal adhesions on the inner side of the membrane. The genes that are altered to cause thoracic aortic aneurysms and aortic dissections encode proteins involved in the structure or function of the SMC elastin – contractile unit. Included in this gene list are the genes encoding protein that are structural components of elastin fibers and microfibrils, FBN1, MFAP5, ELN, and FBLN4. Also included are genes that are structural proteins in the SMC contractile unit, including ACTA2, which encodes SMC-specific α-actin and MYH11, which encodes SMC-specific myosin heavy chain, along with MYLK and PRKG1, which encode kinases that control SMC contraction. Finally, mutations in the gene encoding the protein linking integrin receptors to the contractile filaments, FLNA, also cause thoracic aortic disease. Thus, these data suggest that functional SMC elastin-contractile units are important for maintaining the structural integrity of the aorta.

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“…Interestingly, the clinical presentation of a reported patient affected by a novel EMILIN-1 mutation shows overlapping features with those of patients carrying fibulin-4 or fibulin-5 mutations such as aortic aneurysms, joint laxity, and cutis laxa 22, 46 . One possible hypothesis for this clinical overlap may be that EMILIN-1 is required for proper ECM deposition of fibulin-4 which in turn modulates collagen homeostasis.…”

Section: Discussionmentioning

confidence: 93%

Fibulin-4 deposition requires EMILIN-1 in the extracellular matrix of osteoblasts

Schiavinato

Keene

Imhof

et al. 2017

Sci Rep

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Tissue microenvironments formed by extracellular matrix networks play an important role in regulating tissue structure and function. Extracellular microfibrillar networks composed of fibrillins and their associated ligands such as LTBPs, fibulins, and EMILINs are of particular interest in this regard since they provide a specialized cellular microenvironment guiding proper morphology and functional behavior of specialized cell types. To understand how cellular microenvironments composed of intricate microfibrillar networks influence cell fate decisions in a contextual manner, more information about the spatiotemporal localization, deposition, and function of their components is required. By employing confocal immunofluorescence and electron microscopy we investigated the localization and extracellular matrix deposition of EMILIN-1 and -2 in tissues of the skeletal system such as cartilage and bone as well as in in vitro cultures of osteoblasts. We found that upon RNAi mediated depletion of EMILIN-1 in primary calvarial osteoblasts and MC3T3-E1 cells only fibulin-4 matrix deposition was lost while other fibulin family members or LTBPs remained unaffected. Immunoprecipitation and ELISA-style binding assays confirmed a direct interaction between EMILIN-1 and fibulin-4. Our data suggest a new function for EMILIN-1 which implies the guidance of linear fibulin-4 matrix deposition and thereby fibulin-4 fiber formation.

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Diagnostic Exome Sequencing Identifies a Novel Gene,EMILIN1, Associated with Autosomal‐Dominant Hereditary Connective Tissue Disease

Cited by 41 publications

References 61 publications

A homozygous missense variant in CACNB4 encoding the auxiliary calcium channel beta4 subunit causes a severe neurodevelopmental disorder and impairs channel and non-channel functions

A homozygous missense variant in CACNB4 encoding the auxiliary calcium channel beta4 subunit causes a severe neurodevelopmental disorder and impairs channel and non-channel functions

Structure of the Elastin-Contractile Units in the Thoracic Aorta and How Genes That Cause Thoracic Aortic Aneurysms and Dissections Disrupt This Structure

Fibulin-4 deposition requires EMILIN-1 in the extracellular matrix of osteoblasts

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