Loss-of-Function Variants in EFEMP1 Cause a Recognizable Connective Tissue Disorder Characterized by Cutis Laxa and Multiple Herniations

Verlee, Maxim; Beyens, Aude; Gezdirici, Alper; Güleç, Elif Yılmaz; Pottie, Lore; Feyter, Silke De; Vanhooydonck, Michiel; Tapaneeyaphan, Piyanoot; Symoens, Sofie; Callewaert, Bert

doi:10.3390/genes12040510

Cited by 10 publications

(16 citation statements)

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“…Previous mutations in F3 result in premature stop codons, and in some verified instances, results in nonsense‐mediated mRNA decay (NMD [Driver et al, 2020]). Whether this is true for additional identified F3 nonsense mutations (Verlee et al, 2021) is currently unclear. Thus, it is possible that F3 mutations associated with connective tissue disorders influence disease by diverse mechanisms (i.e., lack of F3, truncated F3, misfolded F3, or dominant‐negative F3).…”

Section: Discussionmentioning

confidence: 99%

“…Fibulin‐3 (F3, encoded by the EFEMP1 gene) is a secreted, disulfide‐rich, extracellular matrix (ECM) glycoprotein of unclear function that is broadly expressed throughout the body (Daniel et al, 2020; Zhang & Marmorstein, 2010). Increasing evidence suggests the involvement of F3 in a variety of diseases ranging from gliomas (Hu et al, 2011), to marfanoid syndrome/connective tissue disorders (Bizzari et al, 2020; Driver et al, 2020; Verlee et al, 2021), to primary open angle glaucoma (Mackay et al, 2015), to age‐related macular degeneration (Meyer et al, 2011), macular dystrophies (Hulleman, 2016; Stone et al, 1999), and general retinal dysfunction (Woodard, Nakahara, et al, 2021). Yet, knowledge of the factors that influence F3 protein homeostasis is limited.…”

Section: Introductionmentioning

confidence: 99%

“…Patients with this homozygous mutation presented with tall stature, inguinal hernias, and advanced bone age, among other features (Bizzari et al, 2020). Due to its mode of inheritance, and because additional studies identified biallelic loss‐of‐function mutations in EFEMP1 in unrelated individuals also with Marfan‐like connective tissue disorders (Driver et al, 2020; Verlee et al, 2021), this C55R mutation likely renders F3 functionally inactive. Yet, how this mutation disrupts the F3 function is unknown.…”

Section: Introductionmentioning

confidence: 99%

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A loss‐of‐function cysteine mutant in fibulin‐3 (EFEMP1) forms aberrant extracellular disulfide‐linked homodimers and alters extracellular matrix composition

et al. 2022

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Fibulin-3 (F3 or EFEMP1) is a disulfide-rich, secreted glycoprotein necessary for maintaining extracellular matrix (ECM) and connective tissue integrity. Two studies have identified distinct autosomal recessive F3 mutations in individuals with Marfan Syndrome-like phenotypes. Herein we characterized how one of these mutations, c.163T>C; p.Cys55Arg (C55R), disrupts F3 secretion, quaternary structure, and function by forming unique extracellular disulfide-linked homodimers. Dual cysteine mutants suggest that the C55R-induced disulfide species forms because of new availability of Cys70 on adjacent F3 monomers. Surprisingly, mutation of single cysteines located near C55 (i.e., C29, C42, C48, C61, C70, C159, and C171) also produced similar extracellular disulfide-linked dimers, suggesting that this is not a phenomenon isolated to the C55R mutant. To assess C55R functionality, F3 knockout (KO) retinal pigmented epithelial (RPE) were generated, followed by reintroduction of wild-type (WT) or C55R F3. F3 KO cells produced lower levels of the ECM remodeling enzyme, matrix metalloproteinase 2 and reduced formation of collagen VI ECM filaments, both of which were partially rescued by WT F3 overexpression. However, C55R F3 was unable to compensate for these same ECM-related defects. Our results highlight the unique behavior of particular cysteine mutations in F3 and uncover potential routes to restore C55R F3 loss-of-function.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A loss‐of‐function cysteine mutant in fibulin‐3 (EFEMP1) forms aberrant extracellular disulfide‐linked homodimers and alters extracellular matrix composition

et al. 2022

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“…Biallelic loss of function variants in EFEMP1 have been reported by three families as the cause of a connective tissue disorder (Bizzari et al, 2020; Driver et al, 2020; Megarbane et al, 2012; Verlee et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

EFEMP1 haploinsufficiency causes a Marfan‐like hereditary connective tissue disorder

Forghani,

Lang,

Rodier

et al. 2024

American J of Med Genetics Pt A

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Phenotypic features of a hereditary connective tissue disorder, including craniofacial characteristics, hyperextensible skin, joint laxity, kyphoscoliosis, arachnodactyly, inguinal hernia, and diverticulosis associated with biallelic pathogenic variants in EFEMP1 have been previously described in four patients. Genome sequencing on a proband and her mother with comparable phenotypic features revealed that both patients were heterozygous for a stop‐gain variant c.1084C>T (p.Arg362*). Complementary RNA‐seq on fibroblasts revealed significantly reduced levels of mutant EFEMP1 transcript. Considering the absence of other molecular explanations, we extrapolated that EFEMP1 could be the cause of the patient's phenotypes. Furthermore, nonsense‐mediated decay was demonstrated for the mutant allele as the principal mechanism for decreased levels of EFEMP1 mRNA. We provide strong clinical and genetic evidence for the haploinsufficiency of EFEMP1 due to nonsense‐medicated decay to cause severe kyphoscoliosis, generalized hypermobility of joints, high and narrow arched palate, and potentially severe diverticulosis. To the best of our knowledge, this is the first report of an autosomal dominant EFEMP1‐associated hereditary connective tissue disorder and therefore expands the phenotypic spectrum of EFEMP1 related disorders.

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“…F3, like many of the other members of its protein family, is widely expressed throughout the human body and plays an important role in regulating the structural and physiological integrity of basement membranes and the ECM [2][3][4] . Accordingly, loss of F3 expression (or loss of F3 function) is associated with reduced pelvic organ support, inguinal hernias, advanced bone age, ECM disruptions, and development of a Marfan-like syndrome [5][6][7][8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

Important anatomical, age-related, and species considerations regarding ocular fibulin-3 (EFEMP1) analysis

Daniel

Hulleman

2022

Preprint

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Purpose: Fibulin-3 (F3) or EFEMP1 is a secreted extracellular matrix glycoprotein implicated in several ocular diseases. Little is known about the native biology of this protein. Thus, our study aims to determine expression and localization characteristics of F3 utilizing a range of mammalian species as well as F3-associated changes with age. Methods: Gene expression analyses for fibulins as well as immunohistochemistry for F3 were conducted in ocular tissue from mice, pigs, non-human primates (NHPs), and humans (n = 3-5). Age-based F3 expression study along with changes in ECM remodeling enzymes was also evaluated in mice. Results: Within the mouse retina, F3 staining was consistent throughout the entirety of the retina (far-periphery, mid-periphery, and central), being enriched in the ganglion cell layer and inner nuclear layer (INL). However, in humans, the F3 staining pattern was quite unique; enriched in the RPE, INL, and outer nuclear layer (ONL) in the peripheral retina, but then shifting to predominantly outer plexiform layer (OPL) staining in the central retina and macula with waning RPE immunoreactivity approaching the fovea. We demonstrate that F3 expression in the mouse retina significantly increases with age, and the levels of extracellular F3 degrading enzymes produced by the RPE and retina (e.g., Mmp2 and Htra1) decrease with age. Conclusions: These findings demonstrate that F3 has distinct species-dependent as well as ocular region-specific expression and localization patterns. We also show that F3 and ECM enzyme dynamics favor F3 accumulation in the retina and RPE with increasing age.

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Loss-of-Function Variants in EFEMP1 Cause a Recognizable Connective Tissue Disorder Characterized by Cutis Laxa and Multiple Herniations

Cited by 10 publications

References 24 publications

A loss‐of‐function cysteine mutant in fibulin‐3 (EFEMP1) forms aberrant extracellular disulfide‐linked homodimers and alters extracellular matrix composition

A loss‐of‐function cysteine mutant in fibulin‐3 (EFEMP1) forms aberrant extracellular disulfide‐linked homodimers and alters extracellular matrix composition

EFEMP1 haploinsufficiency causes a Marfan‐like hereditary connective tissue disorder

Important anatomical, age-related, and species considerations regarding ocular fibulin-3 (EFEMP1) analysis

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