The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat

• Published in: Nature genetics Vol. 38; no. 2; pp. 191 - 196
• Main Authors: Smith, Ursula M, Consugar, Mark, Tee, Louise J, McKee, Brandy M, Maina, Esther N, Whelan, Shelly, Morgan, Neil V, Goranson, Erin, Gissen, Paul, Lilliquist, Stacie, Aligianis, Irene A, Ward, Christopher J, Pasha, Shanaz, Punyashthiti, Rachaneekorn, Malik Sharif, Saghira, Batman, Philip A, Bennett, Christopher P, Woods, C Geoffrey, McKeown, Carole, Bucourt, Martine, Miller, Caroline A, Cox, Phillip, AlGazali, Lihadh, Trembath, Richard C, Torres, Vicente E, Attie-Bitach, Tania, Kelly, Deirdre A, Maher, Eamonn R, Gattone, Vincent H, Harris, Peter C, Johnson, Colin A
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2006; Nature Publishing Group
• Subjects: Abnormalities, Multiple - genetics; Agriculture; Amino acids; Animal Genetics and Genomics; Animals; Base Sequence; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Central nervous system; Cloning; Complications and side effects; Diagnosis; Disease Models, Animal; DNA Mutational Analysis; Exons - genetics; Female; Fundamental and applied biological sciences. Psychology; Gene Function; Gene loci; Gene mutations; Genetic disorders; Genetic Markers; Genetics of eukaryotes. Biological and molecular evolution; Genomics; Haplotypes; Heredity; Human Genetics; Humans; Introns - genetics; Kidneys; letter; Male; Malformations of the nervous system; Medical disorders; Medical sciences; Membrane Proteins; Molecular Sequence Data; Mutation; Mutation - genetics; Neural Tube Defects - genetics; Neurology; Pedigree; Physical Chromosome Mapping; Physiological aspects; Proteins; Proteins - genetics; Rats; Rats, Mutant Strains - genetics; Rats, Wistar; Risk factors; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Syndrome; United Kingdom; Transmembrane protein; Nervous system diseases; Vertebrata; Urinary system disease; Mammalia; Rat; Malformation; Rodentia; Diseases of the osteoarticular system; Digestive diseases; Meckel syndrome; Genetic disease
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng1713

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 polydactyly 1 , 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 hydrocephalus 7 , 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.