Nature Genetics 38, 191 - 196 (2006)
Published online: 15 January 2006; | doi:10.1038/ng1713
The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk ratUrsula M Smith1, 14, Mark Consugar2, 14, Louise J Tee1, Brandy M McKee3, Esther N Maina1, Shelly Whelan2, Neil V Morgan1, Erin Goranson2, Paul Gissen1, 4, Stacie Lilliquist2, Irene A Aligianis1, 5, Christopher J Ward2, Shanaz Pasha1, Rachaneekorn Punyashthiti2, Saghira Malik Sharif6, Philip A Batman7, Christopher P Bennett6, C Geoffrey Woods8, Carole McKeown5, Martine Bucourt9, Caroline A Miller3, Phillip Cox10, Lihadh AlGazali11, Richard C Trembath12, Vicente E Torres2, Tania Attie-Bitach13, Deirdre A Kelly4, Eamonn R Maher1, Vincent H Gattone II3, Peter C Harris2
& Colin A Johnson11
Section of Medical and Molecular Genetics, Division of Reproductive and Child Health, University of Birmingham Medical School, Birmingham B15 2TT, UK. 2
Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota 55904, USA. 3
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. 4
Children's Liver Unit, Princess of Wales Children's Hospital, Steelhouse Lane, Birmingham B4 6NH, UK. 5
Clinical Genetics Unit, Norton Court, Birmingham Women's Hospital, Birmingham B15 2TG, UK. 6
Clinical Genetics, St. James' Hospital, Beckett Street, Leeds LS9 7TF, UK. 7
Department of Histopathology, Bradford Royal Infirmary, Duckworth Lane, Bradford, BD9 6RJ, UK. 8
Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge CB2 2BP, UK. 9
Service d'Anatomopathologie, Hôpital Jean Verdier, 93 Bondy, France. 10
Department of Histopathology, Birmingham Women's Hospital, Birmingham B15 2TG, UK. 11
Faculty of Medicine and Health Sciences, United Arab Emirates University, AlAin, United Arab Emirates. 12
Department of Genetics, University Road, University of Leicester, Leicester LE1 7RH, UK. 13
Département de Génétique et INSERM U-393, Hôpital Necker Enfants-Malades, 149 rue de Sèvres, Paris 75743, France. 14
These authors contributed equally to this work.
Correspondence should be addressed to Colin A Johnson c.a.johnson@bham.ac.uk or Peter C Harris harris.peter@mayo.edu Meckel-Gruber syndrome is a severe autosomal, recessively inherited disorder characterized by bilateral renal cystic dysplasia, developmental defects of the central nervous system (most commonly occipital encephalocele), hepatic ductal dysplasia and cysts and polydactyly1,
2,
3. MKS is genetically heterogeneous, with three loci mapped: MKS1, 17q21-24 (ref. 4); MKS2, 11q13 (ref. 5) and MKS3 (ref. 6). We have refined MKS3 mapping to a 12.67-Mb interval (8q21.13-q22.1) that is syntenic to the Wpk locus in rat, which is a model with polycystic kidney disease, agenesis of the corpus callosum and hydrocephalus7,
8. Positional cloning of the Wpk gene suggested a MKS3 candidate gene, TMEM67, for which we identified pathogenic mutations for five MKS3-linked consanguineous families. MKS3 is a previously uncharacterized, evolutionarily conserved gene that is expressed at moderate levels in fetal brain, liver and kidney but has widespread, low levels of expression. It encodes a 995–amino acid seven-transmembrane receptor protein of unknown function that we have called meckelin.
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