Genes

Editorial

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Open AccessEditorial

Molecular Genetics and Pathogenesis of Ehlers–Danlos Syndrome and Related Connective Tissue Disorders

by Marco Ritelli and Marina Colombi

Genes 2020, 11(5), 547; https://doi.org/10.3390/genes11050547 - 13 May 2020

Cited by 38 | Viewed by 8236

Abstract

Ehlers–Danlos syndromes (EDS) are a group of heritable connective tissue disorders (HCTDs) characterized by a variable degree of skin hyperextensibility, joint hypermobility and tissue fragility. The current EDS classification distinguishes 13 subtypes and 19 different causal genes mainly involved in collagen and extracellular [...] Read more.

Ehlers–Danlos syndromes (EDS) are a group of heritable connective tissue disorders (HCTDs) characterized by a variable degree of skin hyperextensibility, joint hypermobility and tissue fragility. The current EDS classification distinguishes 13 subtypes and 19 different causal genes mainly involved in collagen and extracellular matrix synthesis and maintenance. EDS need to be differentiated from other HCTDs with a variable clinical overlap including Marfan syndrome and related disorders, some types of skeletal dysplasia and cutis laxa. Clinical recognition of EDS is not always straightforward and for a definite diagnosis, molecular testing can be of great assistance, especially in patients with an uncertain phenotype. Currently, the major challenging task in EDS is to unravel the molecular basis of the hypermobile EDS that is the most frequent form, and for which the diagnosis is only clinical in the absence of any definite laboratory test. This EDS subtype, as well as other EDS-reminiscent phenotypes, are currently investigated worldwide to unravel the primary genetic defect and related pathomechanisms. The research articles, case report, and reviews published in this Special Issue focus on different clinical, genetic and molecular aspects of several EDS subtypes and some related disorders, offering novel findings and future research and nosological perspectives. Full article

(This article belongs to the Special Issue Molecular Genetics and Pathogenesis of Ehlers–Danlos Syndrome and Related Connective Tissue Disorders)

Research

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10 pages, 1242 KiB

Open AccessArticle

The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers–Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases

by Camille Kumps, Belinda Campos-Xavier, Yvonne Hilhorst-Hofstee, Carlo Marcelis, Marius Kraenzlin, Nicole Fleischer, Sheila Unger and Andrea Superti-Furga

Genes 2020, 11(4), 420; https://doi.org/10.3390/genes11040420 - 14 Apr 2020

Cited by 10 | Viewed by 10542

Abstract

Recessive loss-of-function variants in SLC39A13, a putative zinc transporter gene, were first associated with a connective tissue disorder that is now called “Ehlers–Danlos syndrome, spondylodysplastic form type 3” (SCD-EDS, OMIM 612350) in 2008. Nine individuals have been described. We describe here four additional [...] Read more.

Recessive loss-of-function variants in SLC39A13, a putative zinc transporter gene, were first associated with a connective tissue disorder that is now called “Ehlers–Danlos syndrome, spondylodysplastic form type 3” (SCD-EDS, OMIM 612350) in 2008. Nine individuals have been described. We describe here four additional affected individuals from three consanguineous families and the follow up of two of the original cases. In our series, cardinal findings included thin and finely wrinkled skin of the hands and feet, characteristic facial features with downslanting palpebral fissures, mild hypertelorism, prominent eyes with a paucity of periorbital fat, blueish sclerae, microdontia, or oligodontia, and—in contrast to most types of Ehlers–Danlos syndrome—significant short stature of childhood onset. Mild radiographic changes were observed, among which platyspondyly is a useful diagnostic feature. Two of our patients developed severe keratoconus, and two suffered from cerebrovascular accidents in their twenties, suggesting that there may be a vascular component to this condition. All patients tested had a significantly reduced ratio of the two collagen-derived crosslink derivates, pyridinoline-to-deoxypyridinoline, in urine, suggesting that this simple test is diagnostically useful. Additionally, analysis of the facial features of affected individuals by DeepGestalt technology confirmed their specificity and may be sufficient to suggest the diagnosis directly. Given that the clinical presentation in childhood consists mainly of short stature and characteristic facial features, the differential diagnosis is not necessarily that of a connective tissue disorder and therefore, we propose that SLC39A13 is included in gene panels designed to address dysmorphism and short stature. This approach may result in more efficient diagnosis. Full article

(This article belongs to the Special Issue Molecular Genetics and Pathogenesis of Ehlers–Danlos Syndrome and Related Connective Tissue Disorders)

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9 pages, 540 KiB

Open AccessArticle

Arterial Elasticity in Ehlers-Danlos Syndromes

by Amanda J. Miller, Jane R. Schubart, Timothy Sheehan, Rebecca Bascom and Clair A. Francomano

Genes 2020, 11(1), 55; https://doi.org/10.3390/genes11010055 - 4 Jan 2020

Cited by 13 | Viewed by 8182

Abstract

Ehlers-Danlos Syndromes (EDS) are a group of heritable disorders of connective tissue (HDCT) characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Orthostatic intolerance (OI) is highly prevalent in EDS however mechanisms linking OI to EDS remain poorly understood. We hypothesize that impaired [...] Read more.

Ehlers-Danlos Syndromes (EDS) are a group of heritable disorders of connective tissue (HDCT) characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Orthostatic intolerance (OI) is highly prevalent in EDS however mechanisms linking OI to EDS remain poorly understood. We hypothesize that impaired blood pressure (BP) and heart rate control is associated with lower arterial stiffness in people with EDS. Orthostatic vital signs and arterial stiffness were assessed in a cohort of 60 people with EDS (49 female, 36 ± 16 years). Arterial elasticity was assessed by central and peripheral pulse wave velocity (PWV). Central PWV was lower in people with EDS compared to reference values in healthy subjects. In participants with EDS, central PWV was correlated to supine systolic BP (r = 0.387, p = 0.002), supine diastolic BP (r = 0.400, p = 0.002), and seated systolic BP (r = 0.399, p = 0.002). There were no significant correlations between PWV and changes in BP or heart rate with standing (p > 0.05). Between EDS types, there were no differences in supine hemodynamics or PWV measures (p > 0.05). These data demonstrate that increased arterial elasticity is associated with lower BP in people with EDS which may contribute to orthostatic symptoms and potentially provides a quantitative clinical measure for future genotype-phenotype investigations. Full article

(This article belongs to the Special Issue Molecular Genetics and Pathogenesis of Ehlers–Danlos Syndrome and Related Connective Tissue Disorders)

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12 pages, 1212 KiB

Open AccessArticle

Novel TNXB Variants in Two Italian Patients with Classical-Like Ehlers-Danlos Syndrome

by Lucia Micale, Vito Guarnieri, Bartolomeo Augello, Orazio Palumbo, Emanuele Agolini, Valentina Maria Sofia, Tommaso Mazza, Antonio Novelli, Massimo Carella and Marco Castori

Genes 2019, 10(12), 967; https://doi.org/10.3390/genes10120967 - 25 Nov 2019

Cited by 11 | Viewed by 6485

Abstract

TNXB-related classical-like Ehlers-Danlos syndrome (TNXB-clEDS) is an ultrarare type of Ehlers-Danlos syndrome due to biallelic null variants in TNXB, encoding tenascin-X. Less than 30 individuals have been reported to date, mostly of Dutch origin and showing a phenotype resembling [...] Read more.

TNXB-related classical-like Ehlers-Danlos syndrome (TNXB-clEDS) is an ultrarare type of Ehlers-Danlos syndrome due to biallelic null variants in TNXB, encoding tenascin-X. Less than 30 individuals have been reported to date, mostly of Dutch origin and showing a phenotype resembling classical Ehlers-Danlos syndrome without atrophic scarring. TNXB-clEDS is likely underdiagnosed due to the complex structure of the TNXB locus, a fact that complicates diagnostic molecular testing. Here, we report two unrelated Italian women with TNXB-clEDS due to compound heterozygosity for null alleles in TNXB. Both presented soft and hyperextensible skin, generalized joint hypermobility and related musculoskeletal complications, and chronic constipation. In addition, individual 1 showed progressive finger contractures and shortened metatarsals, while individual 2 manifested recurrent subconjunctival hemorrhages and an event of spontaneous rupture of the brachial vein. Molecular testing found the two previously unreported c.8278C > T p.(Gln2760*) and the c.(2358 + 1_2359 − 1)_(2779 + 1_2780 − 1)del variants in Individual 1, and the novel c.1150dupG p.(Glu384Glyfs*57) and the recurrent c.11435_11524+30del variants in Individual 2. mRNA analysis confirmed that the c.(2358 + 1_2359 − 1)_(2779 + 1_2780 − 1)del variant causes a frameshift leading to a predicted truncated protein [p.(Thr787Glyfs*40)]. This study refines the phenotype recently delineated in association with biallelic null alleles in TNXB, and adds three novel variants to its mutational repertoire. Unusual digital anomalies seem confirmed as possibly peculiar of TNXB-clEDS, while vascular fragility could be more than a chance association also in this Ehlers-Danlos syndrome type. Full article

(This article belongs to the Special Issue Molecular Genetics and Pathogenesis of Ehlers–Danlos Syndrome and Related Connective Tissue Disorders)

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12 pages, 1875 KiB

Open AccessArticle

Clinical and Molecular Characterization of Classical-Like Ehlers-Danlos Syndrome Due to a Novel TNXB Variant

by Daisy Rymen, Marco Ritelli, Nicoletta Zoppi, Valeria Cinquina, Cecilia Giunta, Marianne Rohrbach and Marina Colombi

Genes 2019, 10(11), 843; https://doi.org/10.3390/genes10110843 - 25 Oct 2019

Cited by 18 | Viewed by 11641

Abstract

The Ehlers-Danlos syndromes (EDS) constitute a clinically and genetically heterogeneous group of connective tissue disorders. Tenascin X (TNX) deficiency is a rare type of EDS, defined as classical-like EDS (clEDS), since it phenotypically resembles the classical form of EDS, though lacking atrophic scarring. [...] Read more.

The Ehlers-Danlos syndromes (EDS) constitute a clinically and genetically heterogeneous group of connective tissue disorders. Tenascin X (TNX) deficiency is a rare type of EDS, defined as classical-like EDS (clEDS), since it phenotypically resembles the classical form of EDS, though lacking atrophic scarring. Although most patients display a well-defined phenotype, the diagnosis of TNX-deficiency is often delayed or overlooked. Here, we described an additional patient with clEDS due to a homozygous null-mutation in the TNXB gene. A review of the literature was performed, summarizing the most important and distinctive clinical signs of this disorder. Characterization of the cellular phenotype demonstrated a distinct organization of the extracellular matrix (ECM), whereby clEDS distinguishes itself from most other EDS subtypes by normal deposition of fibronectin in the ECM and a normal organization of the α5β1 integrin. Full article

(This article belongs to the Special Issue Molecular Genetics and Pathogenesis of Ehlers–Danlos Syndrome and Related Connective Tissue Disorders)

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21 pages, 3674 KiB

Open AccessArticle

Severe Peripheral Joint Laxity is a Distinctive Clinical Feature of Spondylodysplastic-Ehlers-Danlos Syndrome (EDS)-B4GALT7 and Spondylodysplastic-EDS-B3GALT6

by Stefano Giuseppe Caraffi, Ilenia Maini, Ivan Ivanovski, Marzia Pollazzon, Sara Giangiobbe, Maurizia Valli, Antonio Rossi, Silvia Sassi, Silvia Faccioli, Maja Di Rocco, Cinzia Magnani, Belinda Campos-Xavier, Sheila Unger, Andrea Superti-Furga and Livia Garavelli

Genes 2019, 10(10), 799; https://doi.org/10.3390/genes10100799 - 12 Oct 2019

Cited by 11 | Viewed by 10011

Abstract

Variations in genes encoding for the enzymes responsible for synthesizing the linker region of proteoglycans may result in recessive conditions known as “linkeropathies”. The two phenotypes related to mutations in genes B4GALT7 and B3GALT6 (encoding for galactosyltransferase I and II respectively) are similar, [...] Read more.

Variations in genes encoding for the enzymes responsible for synthesizing the linker region of proteoglycans may result in recessive conditions known as “linkeropathies”. The two phenotypes related to mutations in genes B4GALT7 and B3GALT6 (encoding for galactosyltransferase I and II respectively) are similar, characterized by short stature, hypotonia, joint hypermobility, skeletal features and a suggestive face with prominent forehead, thin soft tissue and prominent eyes. The most outstanding feature of these disorders is the combination of severe connective tissue involvement, often manifesting in newborns and infants, and skeletal dysplasia that becomes apparent during childhood. Here, we intend to more accurately define some of the clinical features of B4GALT7 and B3GALT6-related conditions and underline the extreme hypermobility of distal joints and the soft, doughy skin on the hands and feet as features that may be useful as the first clues for a correct diagnosis. Full article

(This article belongs to the Special Issue Molecular Genetics and Pathogenesis of Ehlers–Danlos Syndrome and Related Connective Tissue Disorders)

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12 pages, 13656 KiB

Open AccessArticle

Genotypic Categorization of Loeys-Dietz Syndrome Based on 24 Novel Families and Literature Data

by Letizia Camerota, Marco Ritelli, Anita Wischmeijer, Silvia Majore, Valeria Cinquina, Paola Fortugno, Rosanna Monetta, Laura Gigante, Marfan Syndrome Study Group Tor Vergata University Hospital, Federica Carla Sangiuolo, Giuseppe Novelli, Marina Colombi and Francesco Brancati

Genes 2019, 10(10), 764; https://doi.org/10.3390/genes10100764 - 28 Sep 2019

Cited by 25 | Viewed by 13286

Abstract

Loeys-Dietz syndrome (LDS) is a connective tissue disorder first described in 2005 featuring aortic/arterial aneurysms, dissections, and tortuosity associated with craniofacial, osteoarticular, musculoskeletal, and cutaneous manifestations. Heterozygous mutations in 6 genes (TGFBR1/2, TGFB2/3, SMAD2/3), encoding components of the TGF-β pathway, cause [...] Read more.

Loeys-Dietz syndrome (LDS) is a connective tissue disorder first described in 2005 featuring aortic/arterial aneurysms, dissections, and tortuosity associated with craniofacial, osteoarticular, musculoskeletal, and cutaneous manifestations. Heterozygous mutations in 6 genes (TGFBR1/2, TGFB2/3, SMAD2/3), encoding components of the TGF-β pathway, cause LDS. Such genetic heterogeneity mirrors broad phenotypic variability with significant differences, especially in terms of the age of onset, penetrance, and severity of life-threatening vascular manifestations and multiorgan involvement, indicating the need to obtain genotype-to-phenotype correlations for personalized management and counseling. Herein, we report on a cohort of 34 LDS patients from 24 families all receiving a molecular diagnosis. Fifteen variants were novel, affecting the TGFBR1 (6), TGFBR2 (6), SMAD3 (2), and TGFB2 (1) genes. Clinical features were scored for each distinct gene and matched with literature data to strengthen genotype-phenotype correlations such as more severe vascular manifestations in TGFBR1/2-related LDS. Additional features included spontaneous pneumothorax in SMAD3-related LDS and cervical spine instability in TGFB2-related LDS. Our study broadens the clinical and molecular spectrum of LDS and indicates that a phenotypic continuum emerges as more patients are described, although genotype-phenotype correlations may still contribute to clinical management. Full article

(This article belongs to the Special Issue Molecular Genetics and Pathogenesis of Ehlers–Danlos Syndrome and Related Connective Tissue Disorders)

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20 pages, 2051 KiB

Open AccessArticle

Further Defining the Phenotypic Spectrum of B3GAT3 Mutations and Literature Review on Linkeropathy Syndromes

by Marco Ritelli, Valeria Cinquina, Edoardo Giacopuzzi, Marina Venturini, Nicola Chiarelli and Marina Colombi

Genes 2019, 10(9), 631; https://doi.org/10.3390/genes10090631 - 21 Aug 2019

Cited by 27 | Viewed by 5451

Abstract

The term linkeropathies (LKs) refers to a group of rare heritable connective tissue disorders, characterized by a variable degree of short stature, skeletal dysplasia, joint laxity, cutaneous anomalies, dysmorphism, heart malformation, and developmental delay. The LK genes encode for enzymes that add glycosaminoglycan [...] Read more.

The term linkeropathies (LKs) refers to a group of rare heritable connective tissue disorders, characterized by a variable degree of short stature, skeletal dysplasia, joint laxity, cutaneous anomalies, dysmorphism, heart malformation, and developmental delay. The LK genes encode for enzymes that add glycosaminoglycan chains onto proteoglycans via a common tetrasaccharide linker region. Biallelic variants in XYLT1 and XYLT2, encoding xylosyltransferases, are associated with Desbuquois dysplasia type 2 and spondylo-ocular syndrome, respectively. Defects in B4GALT7 and B3GALT6, encoding galactosyltransferases, lead to spondylodysplastic Ehlers-Danlos syndrome (spEDS). Mutations in B3GAT3, encoding a glucuronyltransferase, were described in 25 patients from 12 families with variable phenotypes resembling Larsen, Antley-Bixler, Shprintzen-Goldberg, and Geroderma osteodysplastica syndromes. Herein, we report on a 13-year-old girl with a clinical presentation suggestive of spEDS, according to the 2017 EDS nosology, in whom compound heterozygosity for two B3GAT3 likely pathogenic variants was identified. We review the spectrum of B3GAT3-related disorders and provide a comparison of all LK patients reported up to now, highlighting that LKs are a phenotypic continuum bridging EDS and skeletal disorders, hence offering future nosologic perspectives. Full article

(This article belongs to the Special Issue Molecular Genetics and Pathogenesis of Ehlers–Danlos Syndrome and Related Connective Tissue Disorders)

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15 pages, 3470 KiB

Open AccessArticle

Defining the Clinical, Molecular and Ultrastructural Characteristics in Occipital Horn Syndrome: Two New Cases and Review of the Literature

by Aude Beyens, Kyaran Van Meensel, Lore Pottie, Riet De Rycke, Michiel De Bruyne, Femke Baeke, Piet Hoebeke, Frank Plasschaert, Bart Loeys, Sofie De Schepper, Sofie Symoens and Bert Callewaert

Genes 2019, 10(7), 528; https://doi.org/10.3390/genes10070528 - 12 Jul 2019

Cited by 24 | Viewed by 9487

Abstract

Occipital horn syndrome (OHS) is a rare connective tissue disorder caused by pathogenic variants in ATP7A, encoding a copper transporter. The main clinical features, including cutis laxa, bony exostoses, and bladder diverticula are attributed to a decreased activity of lysyl oxidase (LOX), a [...] Read more.

Occipital horn syndrome (OHS) is a rare connective tissue disorder caused by pathogenic variants in ATP7A, encoding a copper transporter. The main clinical features, including cutis laxa, bony exostoses, and bladder diverticula are attributed to a decreased activity of lysyl oxidase (LOX), a cupro-enzyme involved in collagen crosslinking. The absence of large case series and natural history studies precludes efficient diagnosis and management of OHS patients. This study describes the clinical and molecular characteristics of two new patients and 32 patients previously reported in the literature. We report on the need for long-term specialized care and follow-up, in which MR angiography, echocardiography and spirometry should be incorporated into standard follow-up guidelines for OHS patients, next to neurodevelopmental, orthopedic and urological follow-up. Furthermore, we report on ultrastructural abnormalities including increased collagen diameter, mild elastic fiber abnormalities and multiple autophagolysosomes reflecting the role of lysyl oxidase and defective ATP7A trafficking as pathomechanisms of OHS. Full article

(This article belongs to the Special Issue Molecular Genetics and Pathogenesis of Ehlers–Danlos Syndrome and Related Connective Tissue Disorders)

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18 pages, 15046 KiB

Open AccessArticle

Transcriptome Profiling of Primary Skin Fibroblasts Reveal Distinct Molecular Features Between PLOD1- and FKBP14-Kyphoscoliotic Ehlers–Danlos Syndrome

by Pei Jin Lim, Uschi Lindert, Lennart Opitz, Ingrid Hausser, Marianne Rohrbach and Cecilia Giunta

Genes 2019, 10(7), 517; https://doi.org/10.3390/genes10070517 - 8 Jul 2019

Cited by 15 | Viewed by 5865

Abstract

Kyphoscoliotic Ehlers–Danlos Syndrome (kEDS) is a rare genetic heterogeneous disease clinically characterized by congenital muscle hypotonia, kyphoscoliosis, and joint hypermobility. kEDS is caused by biallelic pathogenic variants in either PLOD1 or FKBP14. PLOD1 encodes the lysyl hydroxylase 1 enzyme responsible for hydroxylating [...] Read more.

Kyphoscoliotic Ehlers–Danlos Syndrome (kEDS) is a rare genetic heterogeneous disease clinically characterized by congenital muscle hypotonia, kyphoscoliosis, and joint hypermobility. kEDS is caused by biallelic pathogenic variants in either PLOD1 or FKBP14. PLOD1 encodes the lysyl hydroxylase 1 enzyme responsible for hydroxylating lysyl residues in the collagen helix, which undergo glycosylation and form crosslinks in the extracellular matrix thus contributing to collagen fibril strength. FKBP14 encodes a peptidyl-prolyl cis–trans isomerase that catalyzes collagen folding and acts as a chaperone for types III, VI, and X collagen. Despite genetic heterogeneity, affected patients with mutations in either PLOD1 or FKBP14 are clinically indistinguishable. We aim to better understand the pathomechanism of kEDS to characterize distinguishing and overlapping molecular features underlying PLOD1-kEDS and FKBP14-kEDS, and to identify novel molecular targets that may expand treatment strategies. Transcriptome profiling by RNA sequencing of patient-derived skin fibroblasts revealed differential expression of genes encoding extracellular matrix components that are unique between PLOD1-kEDS and FKBP14-kEDS. Furthermore, we identified genes involved in inner ear development, vascular remodeling, endoplasmic reticulum (ER) stress, and protein trafficking that were differentially expressed in patient fibroblasts compared to controls. Overall, our study presents the first transcriptomics data in kEDS revealing distinct molecular features between PLOD1-kEDS and FKBP14-kEDS, and serves as a tool to better understand the disease. Full article

(This article belongs to the Special Issue Molecular Genetics and Pathogenesis of Ehlers–Danlos Syndrome and Related Connective Tissue Disorders)

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11 pages, 1801 KiB

Open AccessArticle

Characterization of Two Novel Intronic Variants Affecting Splicing in FBN1-Related Disorders

by Carmela Fusco, Silvia Morlino, Lucia Micale, Alessandro Ferraris, Paola Grammatico and Marco Castori

Genes 2019, 10(6), 442; https://doi.org/10.3390/genes10060442 - 10 Jun 2019

Cited by 16 | Viewed by 4642

Abstract

FBN1 encodes fibrillin 1, a key structural component of the extracellular matrix, and its variants are associated with a wide range of hereditary connective tissues disorders, such as Marfan syndrome (MFS) and mitral valve–aorta–skeleton–skin (MASS) syndrome. Interpretations of the genomic data and possible [...] Read more.

FBN1 encodes fibrillin 1, a key structural component of the extracellular matrix, and its variants are associated with a wide range of hereditary connective tissues disorders, such as Marfan syndrome (MFS) and mitral valve–aorta–skeleton–skin (MASS) syndrome. Interpretations of the genomic data and possible genotype–phenotype correlations in FBN1 are complicated by the high rate of intronic variants of unknown significance. Here, we report two unrelated individuals with the FBN1 deep intronic variants c.6872-24T>A and c.7571-12T>A, clinically associated with MFS and MASS syndrome, respectively. The individual carrying the c.6872-24T>A variant is positive for aortic disease. Both individuals lacked ectopia lentis. In silico analysis and subsequent mRNA study by RT-PCR demonstrated the effect of the identified variant on the splicing process in both cases. The c.6872-24T>A and c.7571-12T>A variants generate the retention of intronic nucleotides and lead to the introduction of a premature stop codon. This study enlarges the mutation spectrum of FBN1 and points out the importance of intronic sequence analysis and the need for integrative functional studies in FBN1 diagnostics. Full article

(This article belongs to the Special Issue Molecular Genetics and Pathogenesis of Ehlers–Danlos Syndrome and Related Connective Tissue Disorders)

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14 pages, 2369 KiB

Open AccessArticle

Expanding the Clinical and Mutational Spectrum of Recessive AEBP1-Related Classical-Like Ehlers-Danlos Syndrome

by Marco Ritelli, Valeria Cinquina, Marina Venturini, Letizia Pezzaioli, Anna Maria Formenti, Nicola Chiarelli and Marina Colombi

Genes 2019, 10(2), 135; https://doi.org/10.3390/genes10020135 - 12 Feb 2019

Cited by 25 | Viewed by 11969

Abstract

Ehlers-Danlos syndrome (EDS) comprises clinically heterogeneous connective tissue disorders with diverse molecular etiologies. The 2017 International Classification for EDS recognized 13 distinct subtypes caused by pathogenic variants in 19 genes mainly encoding fibrillar collagens and collagen-modifying or processing proteins. Recently, a new EDS [...] Read more.

Ehlers-Danlos syndrome (EDS) comprises clinically heterogeneous connective tissue disorders with diverse molecular etiologies. The 2017 International Classification for EDS recognized 13 distinct subtypes caused by pathogenic variants in 19 genes mainly encoding fibrillar collagens and collagen-modifying or processing proteins. Recently, a new EDS subtype, i.e., classical-like EDS type 2, was defined after the identification, in six patients with clinical findings reminiscent of EDS, of recessive alterations in AEBP1, which encodes the aortic carboxypeptidase–like protein associating with collagens in the extracellular matrix. Herein, we report on a 53-year-old patient, born from healthy second-cousins, who fitted the diagnostic criteria for classical EDS (cEDS) for the presence of hyperextensible skin with multiple atrophic scars, generalized joint hypermobility, and other minor criteria. Molecular analyses of cEDS genes did not identify any causal variant. Therefore, AEBP1 sequencing was performed that revealed homozygosity for the rare c.1925T>C p.(Leu642Pro) variant classified as likely pathogenetic (class 4) according to the American College of Medical Genetics and Genomics (ACMG) guidelines. The comparison of the patient’s features with those of the other patients reported up to now and the identification of the first missense variant likely associated with the condition offer future perspectives for EDS nosology and research in this field. Full article

(This article belongs to the Special Issue Molecular Genetics and Pathogenesis of Ehlers–Danlos Syndrome and Related Connective Tissue Disorders)

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Review

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14 pages, 2496 KiB

Open AccessReview

Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome

by Tomoki Kosho, Shuji Mizumoto, Takafumi Watanabe, Takahiro Yoshizawa, Noriko Miyake and Shuhei Yamada

Genes 2020, 11(1), 43; https://doi.org/10.3390/genes11010043 - 29 Dec 2019

Cited by 27 | Viewed by 13299

Abstract

Musculocontractural Ehlers–Danlos Syndome (mcEDS) is a type of EDS caused by biallelic pathogenic variants in the gene for carbohydrate sulfotransferase 14/dermatan 4-O-sulfotransferase 1 (CHST14/D4ST1, mcEDS-CHST14), or in the gene for dermatan sulfate epimerase (DSE [...] Read more.

Musculocontractural Ehlers–Danlos Syndome (mcEDS) is a type of EDS caused by biallelic pathogenic variants in the gene for carbohydrate sulfotransferase 14/dermatan 4-O-sulfotransferase 1 (CHST14/D4ST1, mcEDS-CHST14), or in the gene for dermatan sulfate epimerase (DSE, mcEDS-DSE). Thus far, 41 patients from 28 families with mcEDS-CHST14 and five patients from four families with mcEDS-DSE have been described in the literature. Clinical features comprise multisystem congenital malformations and progressive connective tissue fragility-related manifestations. This review outlines recent advances in understanding the pathophysiology of mcEDS. Pathogenic variants in CHST14 or DSE lead to reduced activities of relevant enzymes, resulting in a negligible amount of dermatan sulfate (DS) and an excessive amount of chondroitin sulfate. Connective tissue fragility is presumably attributable to a compositional change in the glycosaminoglycan chains of decorin, a major DS-proteoglycan in the skin that contributes to collagen fibril assembly. Collagen fibrils in affected skin are dispersed in the papillary to reticular dermis, whereas those in normal skin are regularly and tightly assembled. Glycosaminoglycan chains are linear in affected skin, stretching from the outer surface of collagen fibrils to adjacent fibrils; glycosaminoglycan chains are curved in normal skin, maintaining close contact with attached collagen fibrils. Homozygous (Chst14^−/−) mice have been shown perinatal lethality, shorter fetal length and vessel-related placental abnormalities. Milder phenotypes in mcEDS-DSE might be related to a smaller fraction of decorin DS, potentially through residual DSE activity or compensation by DSE2 activity. These findings suggest critical roles of DS and DS-proteoglycans in the multisystem development and maintenance of connective tissues, and provide fundamental evidence to support future etiology-based therapies. Full article

(This article belongs to the Special Issue Molecular Genetics and Pathogenesis of Ehlers–Danlos Syndrome and Related Connective Tissue Disorders)

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22 pages, 498 KiB

Open AccessReview

Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes

by Nicola Chiarelli, Marco Ritelli, Nicoletta Zoppi and Marina Colombi

Genes 2019, 10(8), 609; https://doi.org/10.3390/genes10080609 - 12 Aug 2019

Cited by 47 | Viewed by 17411

Abstract

The Ehlers‒Danlos syndromes (EDS) constitute a heterogenous group of connective tissue disorders characterized by joint hypermobility, skin abnormalities, and vascular fragility. The latest nosology recognizes 13 types caused by pathogenic variants in genes encoding collagens and other molecules involved in collagen processing and [...] Read more.

The Ehlers‒Danlos syndromes (EDS) constitute a heterogenous group of connective tissue disorders characterized by joint hypermobility, skin abnormalities, and vascular fragility. The latest nosology recognizes 13 types caused by pathogenic variants in genes encoding collagens and other molecules involved in collagen processing and extracellular matrix (ECM) biology. Classical (cEDS), vascular (vEDS), and hypermobile (hEDS) EDS are the most frequent types. cEDS and vEDS are caused respectively by defects in collagen V and collagen III, whereas the molecular basis of hEDS is unknown. For these disorders, the molecular pathology remains poorly studied. Herein, we review, expand, and compare our previous transcriptome and protein studies on dermal fibroblasts from cEDS, vEDS, and hEDS patients, offering insights and perspectives in their molecular mechanisms. These cells, though sharing a pathological ECM remodeling, show differences in the underlying pathomechanisms. In cEDS and vEDS fibroblasts, key processes such as collagen biosynthesis/processing, protein folding quality control, endoplasmic reticulum homeostasis, autophagy, and wound healing are perturbed. In hEDS cells, gene expression changes related to cell-matrix interactions, inflammatory/pain responses, and acquisition of an in vitro pro-inflammatory myofibroblast-like phenotype may contribute to the complex pathogenesis of the disorder. Finally, emerging findings from miRNA profiling of hEDS fibroblasts are discussed to add some novel biological aspects about hEDS etiopathogenesis. Full article

(This article belongs to the Special Issue Molecular Genetics and Pathogenesis of Ehlers–Danlos Syndrome and Related Connective Tissue Disorders)

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Other

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8 pages, 1368 KiB

Open AccessCase Report

Absence of Collagen Flowers on Electron Microscopy and Identification of (Likely) Pathogenic COL5A1 Variants in Two Patients

by Chloe Angwin, Angela F. Brady, Marina Colombi, David J. P. Ferguson, Rebecca Pollitt, F. Michael Pope, Marco Ritelli, Sofie Symoens, Neeti Ghali and Fleur S. van Dijk

Genes 2019, 10(10), 762; https://doi.org/10.3390/genes10100762 - 27 Sep 2019

Cited by 12 | Viewed by 5515

Abstract

Two probands are reported with pathogenic and likely pathogenic COL5A1 variants (frameshift and splice site) in whom no collagen flowers have been identified with transmission electron microscopy (TEM). One proband fulfils the clinical criteria for classical Ehlers-Danlos syndrome (cEDS) while the other does [...] Read more.

Two probands are reported with pathogenic and likely pathogenic COL5A1 variants (frameshift and splice site) in whom no collagen flowers have been identified with transmission electron microscopy (TEM). One proband fulfils the clinical criteria for classical Ehlers-Danlos syndrome (cEDS) while the other does not and presents with a vascular complication. This case report highlights the significant intrafamilial variability within the cEDS phenotype and demonstrates that patients with pathogenic COL5A1 variants can have an absence of collagen flowers on TEM skin biopsy analysis. This has not been previously reported in the literature and is important when evaluating the significance of a TEM result in patients with clinically suspected cEDS and underscores the relevance of molecular analysis. Full article

(This article belongs to the Special Issue Molecular Genetics and Pathogenesis of Ehlers–Danlos Syndrome and Related Connective Tissue Disorders)

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Molecular Genetics and Pathogenesis of Ehlers–Danlos Syndrome and Related Connective Tissue Disorders

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