Deletion of the 5′exons of<i>COL4A6</i>is not needed for the development of diffuse leiomyomatosis in patients with Alport syndrome

Sá, Maria João Nabais; Fieremans, Nathalie; Brouwer, Arjan P.M. de; Sousa, Rita; Costa, Fernando Teixeira e; Brito, María José; Carvalho, Fernanda; Rodrigues, Márcia; Sousa, Francisco Teixeira de; Felgueiras, Joana; Neves, Fernando; Carvalho, A A S; Ramos, Umbelina; Vizcaíno, José R.; Alves, Susana P.; Carvalho, Filipa; Froyen, Guy; Oliveira, João Paulo

doi:10.1136/jmedgenet-2013-101670

Cited by 21 publications

(11 citation statements)

References 47 publications

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“…Twenty-two (37%) of the 60 probands had a pathogenic mutation in COL4A5, of which 12 (57%) were novel and 9 (43%) had been previously described (Table 1) (5,9,(12)(13)(14)(15)(16)(17). Eighty percent of the probands who presented with all four diagnostic criteria, but only 1 of 3 of those who presented with two or three criteria, had a pathogenic mutation in COL4A5.…”

Section: Methodsmentioning

confidence: 98%

Collagen type IV‐related nephropathies in Portugal: pathogenic COL4A5 mutations and clinical characterization of 22 families

Sá

Sampaio

Oliveira³

et al. 2014

Clinical Genetics

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Alport syndrome (AS) is caused by pathogenic mutations in the genes encoding α3, α4 or α5 chains of collagen IV (COL4A3/COL4A4/COL4A5), resulting in hematuria, chronic renal failure (CRF), sensorineural hearing loss (SNHL) and ocular abnormalities. Mutations in the X-linked COL4A5 gene have been identified in 85% of the families (XLAS). In this study, 22 of 60 probands (37%) of unrelated Portuguese families, with clinical diagnosis of AS and no evidence of autosomal inheritance, had pathogenic COL4A5 mutations detected by Sanger sequencing and/or multiplex-ligation probe amplification, of which 12 (57%) are novel. Males had more severe and earlier renal and extrarenal complications, but microscopic hematuria was a constant finding irrespective of gender. Nonsense and splice site mutations, as well as small and large deletions, were associated with younger age of onset of SNHL in males, and with higher risk of CRF and SNHL in females. Pathogenic COL4A3 or COL4A4 mutations were subsequently identified in more than half of the families without a pathogenic mutation in COL4A5. The lower than expected prevalence of XLAS in Portuguese families warrants the use of next-generation sequencing for simultaneous COL4A3/COL4A4/COL4A5 analysis, as first-tier approach to the genetic diagnosis of collagen type IV-related nephropathies.

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Section: Methodsmentioning

confidence: 98%

Collagen type IV‐related nephropathies in Portugal: pathogenic COL4A5 mutations and clinical characterization of 22 families

Sá

Sampaio

Oliveira³

et al. 2014

Clinical Genetics

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“…Mutations in this gene are associated with the X-linked Alport syndrome, also known as hereditary nephritis (16,17,20,21). Deletions of the 5'-ends of both COL4A5 and COL4A6, including the intergenic region, were found in Alport syndrome associated with diffuse leiomyomatosis (22)(23)(24)(25)(26). Furthermore, whole-genome sequencing analysis showed that a subset of uterine leiomyomas harbored somatic deletions within the COL4A5-COL4A6 locus (27).…”

Section: Discussionmentioning

confidence: 99%

Fusion of the COL4A5 Gene With NR2F2-AS1 in a Hemangioma Carrying a t(X;15)(q22;q26) Chromosomal Translocation

Panagopoulos

Gorunova

Lobmaier

et al. 2020

Cancer Genomics Proteomics

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Background/Aim: Hemangiomas are benign neoplastic proliferations of blood vessels. Cytogenetic information on hemangiomas is limited to four tumors with abnormal karyotypes. We report here a solitary chromosomal translocation and its molecular consequence in a hemangioma. Materials and Methods: A cavernous hemangioma was extirpated from the foot of a 62 years old man and genetically studied with cytogenetic and molecular genetic methodologies. Results: G-Banding analysis of short-term cultured tumor cells yielded the karyotype 46,Y,t(X;15)(q22;q26)[4]/46,XY[12]. RNA sequencing detected fusion of the collagen type IV alpha 5 chain gene (COL4A5 on Xq22.3) with intronic sequences of nuclear receptor subfamily 2 group F member 2 antisense RNA 1 (NR2F2-AS1 on 15q26.2) resulting in a putative COL4A5 truncated protein. The fusion was verified by RT-PCR together with Sanger sequencing and FISH analyses. Conclusion: The involvement of COL4A5 indicates that some hemangiomas have pathogenetic similarities with other benign tumors such as leiomyomas and subungual exostosis. Hemangiomas are benign neoplastic proliferations of blood vessels that may develop in any vascularized tissue. Histologically, they are composed of multiple vascular channels lined with a single layer of endothelium and supported by a fibrous connective tissue scaffold (1). They occur most often in the skin or subcutaneous tissue but may also be found in skeletal muscle, bone, kidneys, lungs, colon, brain, spleen, liver, and pancreas (2-5). Hemangiomas are mostly solitary although multiple hemangioma lesions may occur in individual patients (1). The incidence and prevalence of hemangiomas are difficult to calculate since most lesions are small and asymptomatic. There are several clinical and histological subtypes (6-9). In the present study, we report the genomic abnormalities of a cavernous hemangioma. Ethics statement. The study was approved by the Regional Ethics Committee (Regional komité for medisinsk forskningsetikk Sør-Øst, Norge, http://helseforskning. etikkom.no, 2010/1389/REK sør-øst A). Written informed consent was obtained from the patient. The Ethics Committee's approval included a review of the consent procedure. All patient information has been de-identified.

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“…Diffuse esophageal leiomyomatosis associated with X-linked Alport syndrome has been well described and may imply a contiguous gene deletion involving the 5′exons of COL4A5 and COL4A6 genes [2–4] . Diffuse leiomyomatosis is characterized by circumferential thickening of smooth muscle layers of the esophagus and should be distinguish from leiomyoma which are well circumscribed benign tumor, usually single and rarely multiple [5] .…”

Section: Discussionmentioning

confidence: 99%

Extensive preoperative workup in diffuse esophageal leiomyomatosis associated with Alport syndrome influences surgical treatment: A case report

Dagbert

Pelascini

Pasquer

et al. 2015

International Journal of Surgery Case Reports

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HighlightsDiffuse esophageal leiomyomatosis is frequently associated with Alport syndrome.Only curative option is esophagectomy.Misdiagnosis is common and workup should include endoscopic ultrasonography and 3D-gastric computed tomography for better anatomical delineation.Extensive imaging workup can result in better operative planning.Total esophagectomy should include all diseased tissue and provide good long term quality of life.

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Deletion of the 5′exons ofCOL4A6is not needed for the development of diffuse leiomyomatosis in patients with Alport syndrome

Abstract: These observations suggest that deletion of the 5' exons of COL4A6 and of the common promoter of the COL4A5 and COL4A6 genes is not essential for the development of leiomyomatosis in patients with ATS, and that COL4A5_COL4A6 deletions extending into COL4A6 exon 3 may not result in ATS-DL.

Cited by 21 publications

References 47 publications

Collagen type IV‐related nephropathies in Portugal: pathogenic COL4A5 mutations and clinical characterization of 22 families

Collagen type IV‐related nephropathies in Portugal: pathogenic COL4A5 mutations and clinical characterization of 22 families

Fusion of the COL4A5 Gene With NR2F2-AS1 in a Hemangioma Carrying a t(X;15)(q22;q26) Chromosomal Translocation

Extensive preoperative workup in diffuse esophageal leiomyomatosis associated with Alport syndrome influences surgical treatment: A case report

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