Ullrich disease due to deficiency of collagen VI in the sarcolemma

Ishikawa, H.; Sugie, Kazuma; Murayama, Kumiko; Awaya, Akira; Suzuki, Yu; Noguchi, S.; Hayashi, Yukiko; Nonaka, Ikuya; Nishino, Ichizo

doi:10.1212/01.wnl.0000113023.84421.00

Cited by 88 publications

(71 citation statements)

References 11 publications

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“…In addition, the basement membrane of LH mutant skeletal muscle is detached and loosely bound to muscle fibers. Similarly, in some Ullrich congenital muscular dystrophy patients, collagen VI microfibrils are not linked to muscular basement membrane (44). The reduced amount of type IV collagen in the LH mutant mice may also contribute to the abnormalities of epidermal (16) and muscular basement membranes in these mice.…”

Section: Discussionmentioning

confidence: 98%

Secretion and Assembly of Type IV and VI Collagens Depend on Glycosylation of Hydroxylysines

Sipilä

Ruotsalainen

Sormunen

et al. 2007

Journal of Biological Chemistry

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Most lysines in type IV and VI collagens are hydroxylated and glycosylated, but the functions of these unique galactosylhydroxylysyl and glucosylgalactosylhydroxylysyl residues are poorly understood. The formation of glycosylated hydroxylysines is catalyzed by multifunctional lysyl hydroxylase 3 (LH3) in vivo, and we have used LH3-manipulated mice and cells as models to study the function of these carbohydrates. Collagen biosynthesis contains many co-and post-translational modifications that are unique to collagenous proteins. These modifications include hydroxylation of lysyl residues and their further glycosylation to galactosylhydroxylysyl and glucosylgalactosylhydroxylysyl residues. Lysyl hydroxylase (LH 2 ; E.C. 1.14.11.4) catalyzes the hydroxylation of lysyl residues in the Y-position of the repeating collagen Gly-X-Y triplets (1, 2), and three lysyl hydroxylase isoforms have been characterized: LH1, LH2, and LH3 (3-10).LH3 is a multifunctional enzyme containing, in addition to lysyl hydroxylase activity, collagen galactosyltransferase (E.C. 2.4.1.50) and glucosyltransferase (E.C. 2.4.1.66) activities in vitro (11-13). LH3 is functional in both the endoplasmic reticulum and extracellular space (14), and loss of LH3 leads to early embryonic lethality (15, 16). We have reported recently that LH3 is also multifunctional in vivo and that especially the glucosyltransferase activity of LH3 is essential for normal embryonic development (16).The amount of lysine hydroxylation and glycosylation varies between different collagen types. Type IV and VI collagens are highly hydroxylated and glycosylated, whereas fibrillar collagens, especially types I and III, have much lower levels of these modifications (1, 17, 18). The hydroxylysyl residues have an important role in collagen cross-linking (19,20), but the function of the glycosylation of the hydroxylysyl residues is still poorly understood. The role of glycosylated hydroxylysines in the formation and morphology of collagen fibrils has been debated (21, 22), and we have shown that they are necessary for the correct basement membrane localization of type IV collagen (16).We produced previously three different mouse lines with a manipulated LH3 gene (16). The mice with no or a very low level of the LH3 protein, thus lacking the lysyl hydroxylase and glucosyltransferase activities of LH3, had an embryonic lethal phenotype. The mouse line (LH mutant) with a point mutation that specifically destroys the LH activity of LH3 without affecting glycosyltransferase activities (11) was viable, but showed ultrastructural alterations (16). In this study, we used LH3 knock-out and LH mutant mice and fibroblasts derived from them as a model to investigate the functions of glycosylated hydroxylysines of collagens. This work provides new information about the function of hydroxylysine-linked carbohydrates of collagens, indicating that they play an important role in the secretion of type IV collagen and in the tetramerization and *

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Section: Discussionmentioning

confidence: 98%

Secretion and Assembly of Type IV and VI Collagens Depend on Glycosylation of Hydroxylysines

Sipilä

Ruotsalainen

Sormunen

et al. 2007

Journal of Biological Chemistry

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“…Ishikawa et al 141 considered that these patients could have a primary abnormality of other not yet identified protein interacting with collagen VI in the sarcolemma causing a failure of collagen VI to anchor the basal lamina to the interstitium. however, according to okada et al 138 the possibility of mutations affecting the promoter regions or introns, or of overlooked mutations must be considered in such cases.…”

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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-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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“…Collagen VI is thought to anchor the basement membrane in skeletal muscle by interacting with collagen IV, a major component of the basal lamina 10. In patients with collagen VI deficiency, collagen VI is deficient either completely, which is referred to as complete deficiency, or only absent from the sarcolemma, which is called sarcolemma‐specific collagen VI deficiency (SSCD) 11, 12. In patients with SSCD, collagen VI is present by immunostaining in the interstitium but specifically absent in the sarcolemma.…”

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confidence: 99%

“…Mutations in both COL6A1 and COL6A2 have been identified in some patients with SSCD; however, other patients lack mutations in collagen VI genes and a failure to anchor the basal lamina to the intersititum, possible because of mutations in other molecules has been postulated 12, 13. Identifying the underlying mutation responsible for the collagen VI deficient myopathy affecting the dog in this case report will be important for diagnostic and research purposes and it is the planned next step in the investigation of this condition.…”

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confidence: 99%