Evidence for locus heterogeneity in the Bethlem myopathy and linkage to 2q37

Speer, Marcy C.; Tandan, Rup; Rao, Nagesh; Fries, Timothy J.; Stajich, Jeffrey M.; Bolhuis, P. A.; Jöbsis, G. Joost; Vance, Jeffery M.; Viles, Kristi D.; Sheffield, Karen M.; James, Christi; Kahler, Stephen G.; Pettenati, Mark J.; Gilbert, John R.; Denton, Peter H.; Yamaoka, Larry H.; Pericak‐Vance, Margaret A.

doi:10.1093/hmg/5.7.1043

Cited by 41 publications

(16 citation statements)

References 25 publications

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“…The initial characterization of these collagen VIα1 -/-animals revealed no striking phenotypic changes except mild histological signs of myopathy in skeletal muscle of both homo-and heterozygous mutant animals (19). This myopathy resembled pathologically Bethlem myopathy, a human inherited syndrome correlated with collagen VI genes (21)(22)(23). Subsequent characterization has revealed mitochondrial dysfunction and increased levels of apoptosis in myocytes of these mice (24).…”

Section: Resultsmentioning

confidence: 93%

Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment

Iyengar¹,

Espina²,

Williams³

et al. 2005

J. Clin. Invest.

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The interactions of transformed cells with the surrounding stromal cells are of importance for tumor progression and metastasis. The relevance of adipocyte-derived factors to breast cancer cell survival and growth is well established. However, it remains unknown which specific adipocyte-derived factors are most critical in this process. Collagen VI is abundantly expressed in adipocytes. Collagen -/-mice in the background of the mouse mammary tumor virus/polyoma virus middle T oncogene (MMTV-PyMT) mammary cancer model demonstrate dramatically reduced rates of early hyperplasia and primary tumor growth. Collagen VI promotes its growthstimulatory and pro-survival effects in part by signaling through the NG2/chondroitin sulfate proteoglycan receptor expressed on the surface of malignant ductal epithelial cells to sequentially activate Akt and β-catenin and stabilize cyclin D1. Levels of the carboxyterminal domain of collagen VIα3, a proteolytic product of the fulllength molecule, are dramatically upregulated in murine and human breast cancer lesions. The same fragment exerts potent growth-stimulatory effects on MCF-7 cells in vitro. Therefore, adipocytes play a vital role in defining the ECM environment for normal and tumor-derived ductal epithelial cells and contribute significantly to tumor growth at early stages through secretion and processing of collagen VI.

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Section: Resultsmentioning

confidence: 93%

Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment

Iyengar¹,

Espina²,

Williams³

et al. 2005

J. Clin. Invest.

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“…The only human inherited disorder assigned to this interval of chromosome 2 and characterized by a muscular phenotype is a form of Bethlem myopathy (Speer et al, 1996). Recently, mutations in the COL6A3 gene have been found in patients affected by this disease, excluding a role of the NEU2 gene in the pathogenesis of the disease (Pan et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Cloning and Characterization of NEU2, a Human Gene Homologous to Rodent Soluble Sialidases

Monti

Preti

Rossi³

et al. 1999

Genomics

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“…In addition, a c c o rding to Bertini and Pepe 5 , muscle biopsy fro m Bethlem cases shows non specific changes and an i n c rease of endomysial connective tissue is rare l y o b s e rved. Merc u ry et al 2 1 re p o rted that the degre e of muscle involvement varies according to the deg ree of motor impairment. There f o re in Patient 1 a less amount of muscle changes would be expected.…”

Section: Discussionmentioning

confidence: 99%

Ullrich congenital muscular dystrophy and bethlem myopathy: clinical and genetic heterogeneity

Reed

Ferreira

Liu

et al. 2005

Arq. Neuro-Psiquiatr.

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-Ullrich congenital muscular dystrophy (UCMD), due to mutations in the collagen VI genes, is an autosomal recessive form of CMD, commonly associated with distal joints hyperlaxity and severe course. A mild or moderate involvement can be occasionally observ e d . Objective: To evaluate the clinical picture of CMD patients with Ullrich phenotype who presented decreased or absent collagen VI immunoreactivity on muscular biopsy. Results: Among 60 patients with CMD, two had no expression of collagen V and their clinical involvement was essentially diff e rent: the first (3 years of follow-up) has mild motor difficulty ; the second (8 years of follow-up) never acquired walking and depends on ventilatory support. A molecular stud y, perf o rmed by Pan et al. at the Thomas Jefferson University, demonstrated in the first a known mutation of Bethlem myopathy in COL6A1 and in the second the first dominantly acting mutation in UCMD and the first in COL6A1, previously associated only to Bethlem myopathy, with benign course and dominant inheri t a n c e . Conclusion: Bethlem myopathy should be considered in the diff e rential diagnosis of UCMD, even in patients without fingers contractures; overlap between Ullrich and Bethlem phenotypes can be supposed.KEY WORDS: Ullrich congenital muscular dystrophy, congenital muscular dystrophy, joint hyperlaxity, collagen VI, Bethlem myopathy. D i s t rofia muscular congênita com hiperextensibilidade articular distal (Ullrich) e miopatia de Bethlem: heterogeneidade clínica e genética RESUMO -A distrofia muscular congênita (DMC) com hiperextensibilidade articular distal (fenótipo Ullrich) a ssocia-se a mutações nos genes do colágeno VI e corresponde a um grave quadro congênito de herança autossômica recessiva e curso pro g ressivo, ocasionalmente mostrando menor gravidade. Objetivo: Av a l i a r o quadro clínico dos pacientes com DMC tipo Ullrich que apresentam imunoexpressão baixa ou ausente d o colágeno VI na biópsia muscular. Resultados: E n t re 60 pacientes com DMC, dois mostravam imunomarc ação negativa do colágeno VI. Mostravam-se clinicamente essencialmente diferentes: o primeiro, com 8 anos de idade e três de seguimento mostra leve dificuldade motora; o segundo, com 14 anos de idade e 8 de seguimento, não deambula e apresenta insuficiência respiratória. O estudo molecular, realizado na Thomas Jefferson University por Pan et al., revelou no primeiro, no gene COL6A1, mutação típica da miopatia de Bethlem, que tem curso benigno e herança autossômica dominante; e no segundo a primeira mutação de efeito dominante e do gene COL6A1, previamente associado apenas à miopatia de Bethlem. C o n c l u s ã o : A miopatia de Bethlem deve constar no diagnóstico diferencial da DMC tipo Ullrich, mesmo na ausência das típicas contraturas dos dedos; pode existir sobreposição dos fenótipos Ullrich e Bethlem.PA L AV R A S -C H AVE: distrofia muscular congênita; hiperextensibilidade art i c u l a r, colágeno VI, fenótipo Ullrich, miopatia de Bethlem.

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Evidence for locus heterogeneity in the Bethlem myopathy and linkage to 2q37

Cited by 41 publications

References 25 publications

Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment

Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment

Cloning and Characterization of NEU2, a Human Gene Homologous to Rodent Soluble Sialidases

Ullrich congenital muscular dystrophy and bethlem myopathy: clinical and genetic heterogeneity

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