Bi-allelic AEBP1 mutations in two patients with Ehlers–Danlos syndrome

Syx, Delfien; Wandele, Inge De; Symoens, Sofie; Rycke, Riet De; Hougrand, Olivier; Voermans, Nicol C.; Paepe, Anne De; Malfait, Fransiska

doi:10.1093/hmg/ddz024

Cited by 40 publications

(62 citation statements)

References 18 publications

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“…TNXB deficiency [51], and the recently defined clEDS type 2 caused by biallelic variants in AEBP1 [52]. The clEDS type 1 is generally distinguishable from cEDS for the absence of atrophic scarring [28,45,[53][54][55][56][57], whereas a more severe multisystemic presentation in clEDS type 2 should assist the differential diagnosis with cEDS [43,52,[58][59][60]. The dermatosparaxis (ADAMTS2) [61], cardiac-valvular (COL1A2) [62][63][64], kyphoscoliotic (PLOD1, FKBP14) [65,66], and arthrochalasia (COL1A1, COL1A2) [67,68] EDS subtypes, also sharing with cEDS several cutaneous and articular issues, are mostly distinguishable for the presence of specific hallmarks [1,9,16].…”

Section: Discussionmentioning

confidence: 99%

Multisystemic manifestations in a cohort of 75 classical Ehlers-Danlos syndrome patients: natural history and nosological perspectives

Ritelli

Venturini

Cinquina

et al. 2020

Orphanet J Rare Dis

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Background: The Ehlers-Danlos syndromes (EDS) are rare connective tissue disorders consisting of 13 subtypes with overlapping features including joint hypermobility, skin and generalized connective tissue fragility. Classical EDS (cEDS) is principally caused by heterozygous COL5A1 or COL5A2 variants and rarely by the COL1A1 p.(Arg312Cys) substitution. Current major criteria are (1) skin hyperextensibility plus atrophic scars and (2) generalized joint hypermobility (gJHM). Minor criteria include additional mucocutaneous signs, epicanthal folds, gJHM complications, and an affected firstdegree relative. Minimal criteria prompting molecular testing are major criterion 1 plus either major criterion 2 or 3 minor criteria. In addition to these features, the clinical picture also involves multiple organ systems, but large-scale cohort studies are still missing. This study aimed to investigate the multisystemic involvement and natural history of cEDS through a cross-sectional study on a cohort of 75 molecularly confirmed patients evaluated from 2010 to 2019 in a tertiary referral center. The diagnostic criteria, additional mucocutaneous, osteoarticular, musculoskeletal, cardiovascular, gastrointestinal, uro-gynecological, neuropsychiatric, and atopic issues, and facial/ocular features were ascertained, and feature rates compared by sex and age. Results: Our study confirms that cEDS is mainly characterized by cutaneous and articular involvement, though none of their hallmarks was represented in all cases and suggests a milder multisystemic involvement and a more favorable natural history compared to other EDS subtypes. Abnormal scarring was the most frequent and characteristic sign, skin hyperextensibility and gJHM were less common, all without any sex and age bias; joint instability complications were more recurrent in adults. Some orthopedic features showed a high prevalence, whereas the other issues related to the investigated organ systems were less recurrent with few exceptions and age-related differences.

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Section: Discussionmentioning

confidence: 99%

Multisystemic manifestations in a cohort of 75 classical Ehlers-Danlos syndrome patients: natural history and nosological perspectives

Ritelli

Venturini

Cinquina

et al. 2020

Orphanet J Rare Dis

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“…AEBP1 encodes ACLP, that associates with collagens in the extracelleular matrix (ECM) and is highly expressed in collagen rich tissues like skin, vasculature and connective tissues. 41,42,43,44 In OMIM it can be found under 618000, named EDS classic-like, 2. This new EDS variant is not added in any of the tables 1, 2, and 4.…”

Section: Classification and Nosologymentioning

confidence: 99%

“…Often this is not possible and therefore there is still room for new types. This is, among other things, due to: -the clinical overlap between many of these EDS types Journal of Biomedicine and Translational Research, 5 (2) 2019, [34][35][36][37][38][39][40][41][42][43][44][45][46] -absence of a pathogenic variant in any of the known EDS associated genes in an important proportion of EDS patients. -the presence of associated features which do not fit into one of the existing types.…”

Section: Introductionmentioning

confidence: 99%

Classification, nosology and diagnostics of Ehlers-Danlos syndrome

Hamel

2019

J. Biomed. Transl. Res.

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Ehlers-Danlos syndrome (EDS) comprises a group of heritable connective tissue disorders which has as cardinal features varying degrees of skin hyperextensibility, joint hypermobility, easy bruising and skin fragility. The 2017 New York nosology distinguishes 13 types of EDS, which all, except hypermobile EDS, have a known molecular basis. Hypermobile EDS is recognized as a common and often disabling disorder, incorporating benign joint hypermobility syndrome. EDS needs to be differentiated from other connective tissue disorders, in particular Marfan syndrome, Loeys-Dietz syndrome and cutis laxa. The frequent types of EDS can be diagnosed after careful history taking and clinical examination, but for definite diagnosis molecular confirmation is needed in all types. Management for EDS patients preferably is provided by multidisciplinary teams in expertise centres. After diagnosing EDS genetic counselling is an essential part of the management of patients and their family.

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“…1A). While Cpxm1, Cpxm2, and Aebp1 are all closely related and have been found in recent years to be involved in connective tissue biology [30,31], the function of the third domain of CPD is unclear at this time. It is not unimportant, as it has been shown that this third domain of CPD is necessary for full rescue of an inviable Drosophila CPD deletion [32].…”

Section: Introductionmentioning

confidence: 99%

Biochemical and genetic analysis of Ecm14, a conserved fungal pseudopeptidase

McDonald

Schott

Idowu

et al. 2020

Preprint

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Background. Like most major enzyme families, the M14 family of metallocarboxypeptidases (MCPs) contains a number of pseudoenzymes predicted to lack enzyme activity and with poorly characterized molecular function. The genome of the yeast S. cerevisiae encodes one member of the M14 MCP family, a pseudoenzyme named Ecm14 proposed to function in the extracellular matrix. In order to better understand the function of such pseudoenzymes, we studied the structure and function of Ecm14 in S. cerevisiae. Results. A phylogenetic analysis of Ecm14 in fungi found it to be conserved throughout the ascomycete phylum, with a group of related pseudoenzymes found in basidiomycetes. To investigate the structure and function of this conserved protein, his6-tagged Ecm14 was overexpressed in Sf9 cells and purified. The prodomain of Ecm14 was cleaved in vivo and in vitro by endopeptidases, suggesting an activation mechanism; however, no activity was detectable using standard carboxypeptidase substrates. In order to determine the function of Ecm14 using an unbiased screen, we undertook a synthetic lethal assay. Upon screening approximately 27,000 yeast colonies, twenty-two putative synthetic lethal clones were identified. Further analysis showed many to be synthetic lethal with auxotrophic marker genes and requiring multiple mutations, suggesting that there are few, if any, single S. cerevisiae genes that present synthetic lethal interactions with ecm14. Conclusions. We show in this study that Ecm14, although lacking detectable enzyme activity, is a conserved carboxypeptidase-like protein that is secreted from cells and is processed to a mature form by the action of an endopeptidase. Our study and datasets from other recent large-scale screens suggest a role for Ecm14 in processes such as vesicle-mediated transport and aggregate invasion, a fungal process that has been selected against in modern laboratory strains of S. cerevisiae.

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Bi-allelic AEBP1 mutations in two patients with Ehlers–Danlos syndrome

Cited by 40 publications

References 18 publications

Multisystemic manifestations in a cohort of 75 classical Ehlers-Danlos syndrome patients: natural history and nosological perspectives

Multisystemic manifestations in a cohort of 75 classical Ehlers-Danlos syndrome patients: natural history and nosological perspectives

Classification, nosology and diagnostics of Ehlers-Danlos syndrome

Biochemical and genetic analysis of Ecm14, a conserved fungal pseudopeptidase

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