Abstract
Mutation in ZMPSTE24 gene, encoding a major metalloprotease, leads to defective prelamin A processing and causes type B mandibuloacral dysplasia, as well as the lethal neonatal restrictive dermopathy syndrome. Phenotype severity is correlated with the residual enzyme activity of ZMPSTE24 and accumulation of prelamin A. We had previously demonstrated that a complete loss of function in ZMPSTE24 was lethal in the neonatal period, whereas compound heterozygous mutations including one PTC and one missense mutation were associated with type B mandibuloacral dysplasia. In this study, we report a 30-year longitudinal clinical survey of a patient harboring a novel severe and complex phenotype, combining an early-onset progeroid syndrome and a congenital myopathy with fiber-type disproportion. A unique homozygous missense ZMPSTE24 mutation (c.281T>C, p.Leu94Pro) was identified and predicted to produce two possible ZMPSTE24 conformations, leading to a partial loss of function. Western blot analysis revealed a major reduction of ZMPSTE24, together with the presence of unprocessed prelamin A and decreased levels of lamin A, in the patient's primary skin fibroblasts. These cells exhibited significant reductions in lifespan associated with major abnormalities of the nuclear shape and structure. This is the first report of MAD presenting with confirmed myopathic abnormalities associated with ZMPSTE24 defects, extending the clinical spectrum of ZMPSTE24 gene mutations. Moreover, our results suggest that defective prelamin A processing affects muscle regeneration and development, thus providing new insights into the disease mechanism of prelamin A-defective associated syndromes in general.
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Acknowledgements
We thank Jean-Paul Leroy for his help in the clinical investigation of the patient, Thomas Voit for critical reading and fruitful discussion and the Myocastor study group for its constant support. This work was financially supported by the Institut National de la Santé et de la Recherche Médicale; the Université Pierre et Marie Curie Paris 06; the Université de la Méditerranée, the Centre National de la Recherche Scientifique; the Association Française contre les Myopathies (no. 11057, no. 11034); the European Union Sixth (Euro-laminopathies no. 018690) and Seventh (Myoage no. 223576) Framework Programmes.
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Yaou, R., Navarro, C., Quijano-Roy, S. et al. Type B mandibuloacral dysplasia with congenital myopathy due to homozygous ZMPSTE24 missense mutation. Eur J Hum Genet 19, 647–654 (2011). https://doi.org/10.1038/ejhg.2010.256
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DOI: https://doi.org/10.1038/ejhg.2010.256
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