A comparative analysis of collagen VI production in muscle, skin and fibroblasts from 14 Ullrich congenital muscular dystrophy patients with dominant and recessive COL6A mutations

Jiménez‐Mallebrera, Cecilia; Maioli, Maria Antonietta; Kim, J.; Brown, Susan C.; Feng, Lucy; Lampe, Anne Katrin; Bushby, Kate; Hicks, Debbie; Flanigan, Kevin M.; Bönnemann, Carsten G.; Sewry, Caroline A.; Muntoni, Francesco

doi:10.1016/j.nmd.2006.07.015

Cited by 104 publications

(100 citation statements)

References 30 publications

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“…In 2003, the first heterozygous in-frame deletions acting in a dominantly-negative way was found in the Col6A1 gene 75 in one Brazilian patient with severe Ullrich phenotype 131 ; soon, more patients with a dominantly acting mutation in the Col6A1 were reported [132][133][134] , and finally this same type of mutation has also been found in Ullrich patients with mutations in Col6A2 and Col6A3 genes 132 . heterozygously occurring N-terminal triple helical inframe deletions allow mutant monomers to form dimers but secreted tetramers are abnormal with a consequent dominant negative effect on microfibrillar assembly 132 .…”

Section: Collagen VI Related Muscle Disorders Pathogenesismentioning

confidence: 97%

“…The concept of a spectrum of collagen VI-related disorders with marked clinical and genetic heterogeneity has emerged from the recent advances on the molecular mechanism of both diseases 69 . The complex genotype/phenotype correlations that have been broadly analysed in these two conditions clearly indicate that in both collagen VI-related disorders the main pathomechanism is due to the disruption of collagen VI anchorage to the basal lamina of the muscular fibers 74,75,[120][121][122][123][124][125][126][127][128][129][130][131][132][133][134][135][136][137][138] .…”

Section: Collagen VI Related Muscle Disorders Pathogenesismentioning

confidence: 99%

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Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

Reed

2009

Arq. Neuro-Psiquiatr.

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-The congenital muscular dystrophies (CMDs) are a group of genetically and clinically heterogeneous hereditary myopathies with preferentially autosomal recessive inheritance, that are characterized by congenital hypotonia, delayed motor development and early onset of progressive muscle weakness associated with dystrophic pattern on muscle biopsy. The clinical course is broadly variable and can comprise the involvement of the brain and eyes. From 1994, a great development in the knowledge of the molecular basis has occurred and the classification of CMDs has to be continuously up dated. In the last number of this journal, we presented the main clinical and diagnostic data concerning the different subtypes of CMD. In this second part of the review, we analyse the main reports from the literature concerning the pathogenesis and the therapeutic perspectives of the most common subtypes of CMD: MDC1A with merosin deficiency, collagen VI related CMDs (Ullrich and Bethlem), CMDs with abnormal glycosylation of alpha-dystroglycan (Fukuyama CMD, Muscleeye-brain disease, Walker Warburg syndrome, MDC1C, MDC1D), and rigid spine syndrome, another much rare subtype of CMDs not related with the dystrophin/glycoproteins/extracellular matrix complex.Key WorDs: congenital muscular dystrophy, MDC1A, collagen VI related disorders, glycosylation of alphadystroglycan, Fukuyama DMC, muscle-eye-brain (MeB) disease, Walker-Warburg syndrome, rigid spine syndrome. distrofia muscular congênita. parte ii: revisão da patogênese e perspectivas terapêuticas resumo -As distrofias musculares congênitas (DMCs) são miopatias hereditárias geralmente, porém não exclusivamente, de herança autossômica recessiva, que apresentam grande heterogeneidade genética e clínica. são caracterizadas por hipotonia muscular congênita, atraso do desenvolvimento motor e fraqueza muscular de início precoce associada a padrão distrófico na biópsia muscular. o quadro clínico, de gravidade variável, pode também incluir anormalidades oculares e do sistema nervoso central. A partir de 1994, os conhecimentos sobre genética e biologia molecular das DMCs progrediram rapidamente, sendo a classificação continuamente atualizada. os aspectos clínicos e diagnósticos dos principais subtipos de DMC foram apresentados no número anterior deste periódico, como primeira parte desta revisão. Nesta segunda parte apresentaremos os principais mecanismos patogênicos e as perspectivas terapêuticas dos subtipos mais comuns de DMC: DMC tipo 1A com deficiência de merosina, DMCs relacionadas com alterações do colágeno VI (Ullrich e Bethlem), e DMCs com anormalidades de glicosilação da alfa-distroglicana (DMC Fukuyama, DMC "Muscle-eye-brain" ou MeB, síndrome de Walker Warburg, DMC tipo 1C, DMC tipo 1D). A DMC com espinha rígida, mais rara e não relacionada com alterações do complexo distrofina-glicoproteínas associadas-matriz extracelular também será abordada quanto aos mesmos aspectos patogênicos e terapêuticos.PAlAVrAs-ChAVes: distrofia muscular congênita, merosina, colágeno VI, glicosila...

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Section: Collagen VI Related Muscle Disorders Pathogenesismentioning

confidence: 97%

Section: Collagen VI Related Muscle Disorders Pathogenesismentioning

confidence: 99%

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

Reed

2009

Arq. Neuro-Psiquiatr.

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“…Based on the mutation, different mechanisms can be predicted such as: (1) loss-of-function for mutations perturbing triple helix formation, intracellular assembly or ColVI secretion; (2) dominant negative effect for mutations giving rise to abnormal ColVI polypeptides secreted in the ECM; and (3) haploinsufficiency for mutations affecting mRNA stability, with a decreased synthesis of normal ColVI. The effect of specific COL6 mutations has been investigated by in vitro studies (Lamande et al 1999(Lamande et al , 2002Sasaki et al 2000;Zhang et al 2002;Jimenez-Mallebrera et al 2006;Baker et al 2007;Tooley et al 2010), which provided relevant clues on their effect at the protein level. However, there is no conclusive evidence on the genotype -phenotype correlation for BM and UCMD, which may represent a clinical continuum rather than strictly separate entities Lampe and Bushby 2005;Bönnemann 2011).…”

Section: Collagen Vi-related Muscle Diseasesmentioning

confidence: 99%

Mitochondrial Dysfunction and Defective Autophagy in the Pathogenesis of Collagen VI Muscular Dystrophies

Bernardi

Bonaldo

2013

Cold Spring Harbor Perspectives in Biology

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Myosclerosis are diseases caused by mutations in the genes encoding the extracellular matrix protein collagen VI. A dystrophic mouse model, where collagen VI synthesis was prevented by targeted inactivation of the Col6a1 gene, allowed the investigation of pathogenesis, which revealed the existence of a Ca 2þ -mediated dysfunction of mitochondria and sarcoplasmic reticulum, and of defective autophagy. Key events are dysregulation of the mitochondrial permeability transition pore, an inner membrane high-conductance channel that for prolonged open times causes mitochondrial dysfunction, and inadequate removal of defective mitochondria, which amplifies the damage. Consistently, the Col6a1 2/2 myopathic mice could be cured through inhibition of cyclophilin D, a matrix protein that sensitizes the pore to opening, and through stimulation of autophagy. Similar defects contribute to disease pathogenesis in patients irrespective of the genetic lesion causing the collagen VI defect. These studies indicate that permeability transition pore opening and defective autophagy represent key elements for skeletal muscle fiber death, and provide a rationale for the use of cyclosporin A and its nonimmunosuppressive derivatives in patients affected by collagen VI myopathies, a strategy that holds great promise for treatment.

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“…Supplementation of the cblC cultures with HOCbl downregulated its expression. Mutations in the genes that code for collagen VI subunits result in Ullrich syndrome [ 77 ] and Bethlem myopathy [ 78 ], an autosomal dominant disorder. An upregulation of collagen VI α 2 was also noted in a patient with cblD disease [ 74 ].…”

Section: Cytoskeleton: Assembly and Remodelingmentioning

confidence: 99%

Proteomics of vitamin B12 processing

Hannibal

DiBello

Jacobsen³

2013

Clinical Chemistry and Laboratory Medicine

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The causes of cobalamin (B 12 , Cbl) deficiency are multifactorial. Whether nutritional due to poor dietary intake, or functional due to impairments in absorption or intracellular processing and trafficking events, the major symptoms of Cbl deficiency include megaloblastic anemia, neurological deterioration and in extreme cases, failure to thrive and death. The common biomarkers of Cbl deficiency (hyperhomocysteinemia and methylmalonic acidemia) are extremely valuable diagnostic indicators of the condition, but little is known about the changes that occur at the protein level. A mechanistic explanation bridging the physiological changes associated with functional B 12 deficiency with its intracellular processers and carriers is lacking. In this article, we will cover the effects of B 12 deficiency in a cblC -disrupted background (also referred to as MMACHC) as a model of functional Cbl deficiency. As will be shown, major protein changes involve the cytoskeleton, the neurological system as well as signaling and detoxification pathways. Supplementation of cultured MMACHC-mutant cells with hydroxocobalamin (HOCbl) failed to restore these variants to the normal phenotype, suggesting that a defective Cbl processing pathway produces irreversible changes at the protein level.

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A comparative analysis of collagen VI production in muscle, skin and fibroblasts from 14 Ullrich congenital muscular dystrophy patients with dominant and recessive COL6A mutations

Cited by 104 publications

References 30 publications

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

Mitochondrial Dysfunction and Defective Autophagy in the Pathogenesis of Collagen VI Muscular Dystrophies

Proteomics of vitamin B12 processing

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