Paternal germline mosaicism in collagen VI related myopathies

Armaroli, Annarita; Trabanelli, Cecilia; Scotton, C.; Venturoli, A.; Selvatici, Rita; Brisca, Giacomo; Merlini, Luciano; Bruno, Claudio; Ferlini, Alessandra; Gualandi, Francesca

doi:10.1016/j.ejpn.2015.04.002

Cited by 17 publications

(29 citation statements)

References 12 publications

(6 reference statements)

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“…Two piriformis and two pedidium tendons were obtained from healthy volunteers subjected to surgical intervention. Sample processing followed previously described procedures [16]. All subjects gave their informed consent before they participated in the study.…”

Section: Patientsmentioning

confidence: 99%

“…The media recovered from the different culture conditions were concentrated with Vivaspin sample concentrators (Vivaspin 2 MWCO10000, GE Healthcare, Amersham, Pittsburgh, PA, USA) according to the manufacturer's operating procedures. Cell lysates and concentrated culture media were resolved by standard SDS-PAGE, electro-blotted onto a nitrocellulose membrane, and incubated with antibodies against α3(VI), α1(VI), and α5(VI) chains [16]; NG2 proteoglycan antibody (Millipore) was used as previously reported [16]; tenomodulin and actin (Santa Cruz) were used as loading controls. Primary antibodies were followed by incubation with anti-mouse or anti-rabbit horseradish peroxidase (HRP)-conjugated secondary antibodies.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…Given the role of the collagen VI-NG2 axis in stabilizing the lagging end of cells during migration [16], we subjected BM and UCMD tendon fibroblasts to scratch wound assay, to study cell motility and migration in response to in vitro injury. Confluent tendon fibroblast cultures were scratched and after six hours were studied by immunofluorescence analysis.…”

Section: Disruption Of Collagen Vi-ng2 Axis Affects Bm and Ucmd Cell mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…While we previously demonstrated that collagen VI, through its interaction with the CSPG4/NG2 transmembrane proteoglycan, regulates specific cellular functions, including cell polarization and migration, the impact of mutations in collagen VI genes in human tendon function has been poorly explored, mainly due to the difficulty in obtaining biopsies from patients' tendons [16]. So far, only one study on tendon fibroblasts of a UCMD patient is reported [16]. In this paper we confirm the matrix tendon alterations in another UCMD patient with a mutation in the COL6A1 gene and show for the first time the presence of a dysfunctional fibrillogenesis and an altered cell behavior in tendon fibroblasts of a patient with BM phenotype.…”

Section: Introductionmentioning

confidence: 99%

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Tendon Extracellular Matrix Remodeling and Defective Cell Polarization in the Presence of Collagen VI Mutations

Antoniel

Traina

Merlini

et al. 2020

Cells

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Mutations in collagen VI genes cause two major clinical myopathies, Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD), and the rarer myosclerosis myopathy. In addition to congenital muscle weakness, patients affected by collagen VI-related myopathies show axial and proximal joint contractures, and distal joint hypermobility, which suggest the involvement of tendon function. To gain further insight into the role of collagen VI in human tendon structure and function, we performed ultrastructural, biochemical, and RT-PCR analysis on tendon biopsies and on cell cultures derived from two patients affected with BM and UCMD. In vitro studies revealed striking alterations in the collagen VI network, associated with disruption of the collagen VI-NG2 (Collagen VI-neural/glial antigen 2) axis and defects in cell polarization and migration. The organization of extracellular matrix (ECM) components, as regards collagens I and XII, was also affected, along with an increase in the active form of metalloproteinase 2 (MMP2). In agreement with the in vitro alterations, tendon biopsies from collagen VI-related myopathy patients displayed striking changes in collagen fibril morphology and cell death. These data point to a critical role of collagen VI in tendon matrix organization and cell behavior. The remodeling of the tendon matrix may contribute to the muscle dysfunction observed in BM and UCMD patients.

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Section: Patientsmentioning

confidence: 99%

Section: Western Blot Analysismentioning

confidence: 99%

Section: Disruption Of Collagen Vi-ng2 Axis Affects Bm and Ucmd Cell mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Tendon Extracellular Matrix Remodeling and Defective Cell Polarization in the Presence of Collagen VI Mutations

Antoniel

Traina

Merlini

et al. 2020

Cells

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Gonadal mosaicism in ARID1B gene causes intellectual disability and dysmorphic features in three siblings

Ben-Salem

Sobreira

Akawi

et al. 2015

American J of Med Genetics Pt A

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The gene encoding the AT-rich interaction domain-containing protein 1B (ARID1B) has recently been shown to be one of the most frequently mutated genes in patients with intellectual disability (ID). The phenotypic spectrums associated with variants in this gene vary widely ranging for mild to severe nonspecific ID to Coffin–Siris syndrome. In this study, we evaluated three children from a consanguineous Emirati family affected with ID and dysmorphic features. Genomic DNA from all affected siblings was analyzed using CGH array and whole-exome sequencing (WES). Based on a recessive mode of inheritance, homozygous or compound heterozygous variants shared among all three affected children could not be identified. However, further analysis revealed a heterozygous variant (c.4318C>T; p.Q1440*) in the three affected children in an autosomal dominant ID causing gene, ARID1B. This variant was absent in peripheral blood samples obtained from both parents and unaffected siblings. Therefore, we propose that the most likely explanation for this situation is that one of the parents is a gonadal mosaic for the variant. To the best of our knowledge, this is the first report of a gonadal mosaicism inheritance of an ARID1B variant leading to familial ID recurrence.

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Combined effects of two mutations in von Willebrand disease 2M phenotype

Woods

Paiva

Kempfer

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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Essentials Compound heterozygosity causes a VWD2M phenotype in a child with severe bleeding symptoms.p.P1648fs*45 changes the folding of A2 domain altering VWF binding to GPIbα and type VI collagen.p.P1648fs*45 was considered as an apparent de novo mutation; AS‐PCR revealed paternal mosaicism.Bleeding score and DDAVP's response were worse than those seen in VWD2M heterozygous controls. BackgroundType 2M von Willebrand disease (VWD2M) is usually characterized by VWF:RCo/VWF:Ag<0.6 and normal multimeric profile; desmopressin (DDAVP) challenge test commonly shows poor response of VWF:RCo.ObjectiveWe describe the bleeding tendency and the laboratory phenotype in a patient carrying two heterozygous mutations affecting VWF‐A1 domain and VWF‐A2 domain.Subjects/methodsA 12‐year‐old patient (O blood group) with severe hemorrhagic tendency was phenotypically and genotypically analyzed; his parents were also studied.ResultsThe proband showed decrease FVIII:C, VWF:RCo/VWF:Ag, and VWF:CB6/VWF:Ag ratios, but normal platelet count, VWF:CB1/VWF:Ag ratio, VWFpp and multimeric pattern, suggesting a VWD2M phenotype. The DDAVP challenge test, compared to controls (VWD2M patients with mutations in VWF‐A1 domain), showed lower increase of FVIII:C and VWF:Ag than in heterozygous, but very similar to homozygous control. Two mutations were found in heterozygous and trans presentation: p.Pro1648fs*45 and a novel missense mutation, p.Arg1426Cys. The mother was p.Arg1426Cys heterozygous carrier, with few clinical symptoms. The father was asymptomatic, with no mutations. The p.Pro1648fs*45 was considered an apparent de novo mutation; proband's AS‐PCR revealed mosaicism in the paternal allele. According to the predicted models, p.Arg1426Cys would not be affecting the binding of GPIbα to A1 domain, whereas p.Pro1648fs*45 seems to modify the folding of A2 domain, and in this way, it would affect the binding to GPIbα and type VI collagen. We believe that the combination of these two heterozygous mutations, in a child with O blood group, could result in a defective phenotype enhancer.

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Paternal germline mosaicism in collagen VI related myopathies

Cited by 17 publications

References 12 publications

Tendon Extracellular Matrix Remodeling and Defective Cell Polarization in the Presence of Collagen VI Mutations

Tendon Extracellular Matrix Remodeling and Defective Cell Polarization in the Presence of Collagen VI Mutations

Gonadal mosaicism in ARID1B gene causes intellectual disability and dysmorphic features in three siblings

Combined effects of two mutations in von Willebrand disease 2M phenotype

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