Abstract
Muscle–eye–brain disease (MEB, OMIM 253280) is an autosomal recessive disorder characterized by a distinct triad of congenital muscular dystrophy, structural eye abnormalities, and cobblestone lissencephaly. Clinically, MEB patients present with early onset muscular hypotonia, severely compromised motor development, and mental retardation. Magnetic resonance imaging reveals a lissencephaly type II with hypoplasia of the brainstem and cerebellum. MEB is associated with mutations in the gene for protein O-mannose beta-1,2-N-acetylglucosaminyltransferase (POMGnT1, OMIM 606822). In this paper, we report the clinical findings of nine MEB patients from eight families. Eight of the nine patients presented typical features of MEB. However, a broad phenotypic variability was observed, ranging from two patients with severe autistic features to another patient with an unusually mild phenotype, initially diagnosed as congenital muscular dystrophy. Furthermore, severe hydrocephalus was reported in two families during a previous pregnancy, emphasizing the phenotypic overlap with Walker–Warburg syndrome. In addition to three previously reported mutations, we identified six novel POMGnT1 mutations (one missense, five truncating) in the present patient cohort. Our data suggest mutational hotspots within the minimal catalytic domain at arginine residue 442 (exon 16) and in intron 17. It is interesting to note that all mutations analyzed so far result in a complete loss of enzyme activity. Therefore, we conclude that the type and position of the POMGnT1 mutations are not of predictive value for the clinical severity. This supports the notion that additional environmental and/or genetic factors may contribute to the observed broad spectrum of POMGnT1-associated phenotypes.
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Acknowledgments
We thank the families for their participation in this study, B.H.F. Weber for his support and scientific advice, and C. Mai and F. Koehler for excellent technical assistance. This work was supported in part by the “Regensburger Forschungsförderung der Medizinischen Fakultät” (ReForM; University of Regensburg, Germany), the Joint German-Israeli Research Program of the Federal Ministry of Education and Research (BMBF) and the Ministry of Science and Technology (MOST) “Towards neural stem cell based therapies: the impact of neuronal migration” (BMBF no. 01GA0510). MCW and HL are members of the German Muscular Dystrophy Network (MD-NET; 01GM0601; www.md-net.org) funded by the German Ministry of Education and Research (BMBF, Bonn, Germany). MD-NET is a partner of TREAT-NMD (EC, 6th FP, proposal no. 036825; www.treat-nmd.eu).
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Summary of novel POMGnT1 mutations.
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POMGnT1 missense mutations at codon 442: wild-type sequence (a), patient 2a homozygous Arg442Cys (b), and patient 7 homozygous Arg442His (c). MspI restriction fragment length polymorphism and sequence demonstrating the presence of the POMGnT1 mutation c.1540−2A>G in homozygous state in patient 5 and in heterozygous state in both parents but not in the control (d). Patient 6, homozygous for the frameshift mutation c.1350_1354delCTGGG in exon 16 of the POMGnT1 gene; (wild-type in upper lanes, e) (PDF 269 kb)
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Hehr, U., Uyanik, G., Gross, C. et al. Novel POMGnT1 mutations define broader phenotypic spectrum of muscle–eye–brain disease. Neurogenetics 8, 279–288 (2007). https://doi.org/10.1007/s10048-007-0096-y
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DOI: https://doi.org/10.1007/s10048-007-0096-y