Correlation of enzyme activity and clinical phenotype in POMT1-associated dystroglycanopathies

Lommel, Mark; Çırak, Sebahattin; Willer, Tobias; Hermann, R; Uyanık, Gökhan; Bokhoven, Hans van; Kørner, Camilla Julie; Voït, Thomas; Barić, Ivo; Hehr, Ute; Strahl, Sabine

doi:10.1212/wnl.0b013e3181c919d6

Cited by 32 publications

(27 citation statements)

References 26 publications

(28 reference statements)

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“…On the other hand, measurement of POMT activity using dermal fibroblasts from POMT1-mutated patients showed that clinical phenotype severity is inversely correlated with POMT1 activity. 35 A direct correlation between mannosyltransferase activity and clinical severity, however, does not seem to apply to heart involvement, which in our patients appears possible with very different degrees of neuromuscular severity, and with both complete and partial glycosylation defects (detected in the skeletal muscle).…”

Section: Discussioncontrasting

confidence: 57%

Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy

et al. 2012

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Protein-o-mannosyl transferase 1 (POMT1) is a glycosyltransferase involved in a-dystroglycan (a-DG) glycosylation. Clinical phenotype in POMT1-mutated patients ranges from congenital muscular dystrophy (CMD) with structural brain abnormalities, to limb-girdle muscular dystrophy (LGMD) with microcephaly and mental retardation, to mild LGMD. No cardiac involvement has until now been reported in POMT1-mutated patients. We report three patients who harbored compound heterozygous POMT1 mutations and showed left ventricular (LV) dilation and/or decrease in myocardial contractile force: two had a LGMD phenotype with a normal or close-to-normal cognitive profile and one had CMD with mental retardation and normal brain MRI. Reduced or absent a-DG immunolabeling in muscle biopsies were identified in all three patients. Bioinformatic tools were used to study the potential effect of POMT1-detected mutations. All the detected POMT1 mutations were predicted in silico to interfere with protein folding and/or glycosyltransferase function. The report on the patients described here has widened the clinical spectrum associated with POMT1 mutations to include cardiomyopathy. The functional impact of known and novel POMT1 mutations was predicted with a bioinformatics approach, and results were compared with previous in vitro studies of protein-o-mannosylase function.

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Section: Discussioncontrasting

confidence: 57%

Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy

et al. 2012

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“…With respect to FKTN, a patient homozygous for an early nonsense mutation died at 4.5 months, and patients with compound heterozygosity with the Japanese founder mutation and nonsense, frameshift, or exon-skipping mutations are clinically more severely affected than those homozygous for the founder mutation, indicating that disease severity is dependent on the nature of the gene mutation (9,56,57). While we do not yet know the specific activity of FKTN in the αDG processing pathway, we presume that the degree of αDG dysfunction and the disruption of FKTN protein activity will also be positively correlated to the FKTN gene mutation, as has been shown for POMT1 and POMGnT1 enzyme activity in patient cells (58,59).…”

Section: Discussionmentioning

confidence: 90%

Mouse fukutin deletion impairs dystroglycan processing and recapitulates muscular dystrophy

Beedle¹,

Turner²,

Saito³

et al. 2012

J. Clin. Invest.

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Dystroglycan is a transmembrane glycoprotein that links the extracellular basement membrane to cytoplasmic dystrophin. Disruption of the extensive carbohydrate structure normally present on α-dystroglycan causes an array of congenital and limb girdle muscular dystrophies known as dystroglycanopathies. The essential role of dystroglycan in development has hampered elucidation of the mechanisms underlying dystroglycanopathies. Here, we developed a dystroglycanopathy mouse model using inducible or muscle-specific promoters to conditionally disrupt fukutin (Fktn), a gene required for dystroglycan processing. In conditional Fktn-KO mice, we observed a near absence of functionally glycosylated dystroglycan within 18 days of gene deletion. Twentyweek-old KO mice showed clear dystrophic histopathology and a defect in glycosylation near the dystroglycan O-mannose phosphate, whether onset of Fktn excision driven by muscle-specific promoters occurred at E8 or E17. However, the earlier gene deletion resulted in more severe phenotypes, with a faster onset of damage and weakness, reduced weight and viability, and regenerating fibers of smaller size. The dependence of phenotype severity on the developmental timing of muscle Fktn deletion supports a role for dystroglycan in muscle development or differentiation. Moreover, given that this conditional Fktn-KO mouse allows the generation of tissue-and timingspecific defects in dystroglycan glycosylation, avoids embryonic lethality, and produces a phenotype resembling patient pathology, it is a promising new model for the study of secondary dystroglycanopathy.

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“…1E). The observed phenotypic variations could be caused by differences in POMT activity, given that low enzymatic activity was detected for human and zebrafish POMT2 in the absence of POMT1 (13,21). In addition, compared with the levels of the Pomt2 maternal mRNA during the transition from oocyte to morula, the levels of Pomt1 mRNA were strikingly high ( Fig.…”

Section: Resultsmentioning

confidence: 96%

Protein O-mannosylation is crucial for E-cadherin–mediated cell adhesion

Lommel¹,

Winterhalter

Willer³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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In recent years protein O-mannosylation has become a focus of attention as a pathomechanism underlying severe congenital muscular dystrophies associated with neuronal migration defects. A key feature of these disorders is the lack of O-mannosyl glycans on α-dystroglycan, resulting in abnormal basement membrane formation. Additional functions of O-mannosylation are still largely unknown. Here, we identify the essential cell-cell adhesion glycoprotein epithelial (E)-cadherin as an O-mannosylated protein and establish a functional link between O-mannosyl glycans and cadherin-mediated cell-cell adhesion. By genetically and pharmacologically blocking protein O-mannosyltransferases, we found that this posttranslational modification is essential for preimplantation development of the mouse embryo. O-mannosylation-deficient embryos failed to proceed from the morula to the blastocyst stage because of defects in the molecular architecture of cell-cell contact sites, including the adherens and tight junctions. Using mass spectrometry, we demonstrate that O-mannosyl glycans are present on E-cadherin, the major cell-adhesion molecule of blastomeres, and present evidence that this modification is generally conserved in cadherins. Further, the use of newly raised antibodies specific for an O-mannosyl-conjugated epitope revealed that these glycans are present on early mouse embryos. Finally, our cell-aggregation assays demonstrated that O-mannosyl glycans are crucial for cadherin-based cell adhesion. Our results redefine the significance of O-mannosylation in humans and other mammals, showing the immense impact of cadherins on normal as well as pathogenic cell behavior.POMT2 | mouse preimplantation development | protein-glycosylation | O-glycans | POMT1

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Correlation of enzyme activity and clinical phenotype in POMT1-associated dystroglycanopathies

Cited by 32 publications

References 26 publications

Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy

Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy

Mouse fukutin deletion impairs dystroglycan processing and recapitulates muscular dystrophy

Protein O-mannosylation is crucial for E-cadherin–mediated cell adhesion

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