title: Novel POMGnT1 mutations define broader phenotypic spectrum of muscle-eye-brain disease.
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.
authors: Center for Human Genetics and Department of Human Genetics, University of Regensburg, Universitätklinikum D3, Franz-Josef-Strauss-Allee 11, Regensburg 93053, Germany. info@humangenetik-regensburg.de
authors: Ute
authors: U
authors: Hehr
authors: Goekhan
authors: G
authors: Uyanik
authors: Claudia
authors: C
authors: Gross
authors: Maggie C
authors: MC
authors: Walter
authors: Axel
authors: A
authors: Bohring
authors: Monika
authors: M
authors: Cohen
authors: Barbara
authors: B
authors: Oehl-Jaschkowitz
authors: Lynne M
authors: LM
authors: Bird
authors: Ghiat M
authors: GM
authors: Shamdeen
authors: Ulrich
authors: U
authors: Bogdahn
authors: Gerhard
authors: G
authors: Schuierer
authors: Haluk
authors: H
authors: Topaloglu
authors: Ludwig
authors: L
authors: Aigner
authors: Hanns
authors: H
authors: Lochmüller
authors: Jürgen
authors: J
authors: Winkler
mesh_terms: D000293:Adolescent; D000818:Animals; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D054222:Cobblestone Lissencephaly / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D004247:DNA / Q000235:genetics; D049030:Dystroglycans / Q000378:metabolism; D005124:Eye Abnormalities / Q000201:enzymology* / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009136:Muscular Dystrophies / Q000151:congenital / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D020125:Mutation, Missense; D017351:N-Acetylglucosaminyltransferases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*; D010641:Phenotype; D013577:Syndrome
chemical_list: C483081:DAG1 protein, human; D049030:Dystroglycans; D004247:DNA; D017351:N-Acetylglucosaminyltransferases; C443106:protein O-mannose beta-1,2-N-acetylglucosaminyltransferase