TY - JOUR
T1 - The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat
AU - Smith, Ursula M.
AU - Consugar, Mark
AU - Tee, Louise J.
AU - McKee, Brandy M.
AU - Maina, Esther N.
AU - Whelan, Shelly
AU - Morgan, Neil V.
AU - Goranson, Erin
AU - Gissen, Paul
AU - Lilliquist, Stacie
AU - Aligianis, Irene A.
AU - Ward, Christopher J.
AU - Pasha, Shanaz
AU - Punyashthiti, Rachaneekorn
AU - Sharif, Saghira Malik
AU - Batman, Philip A.
AU - Bennett, Christopher P.
AU - Woods, C. Geoffrey
AU - McKeown, Carole
AU - Bucourt, Martine
AU - Miller, Caroline A.
AU - Cox, Phillip
AU - AlGazali, Lihadh
AU - Trembath, Richard C.
AU - Torres, Vicente E.
AU - Attie-Bitach, Tania
AU - Kelly, Deirdre A.
AU - Maher, Eamonn R.
AU - Gattone, Vincent H.
AU - Harris, Peter C.
AU - Johnson, Colin A.
N1 - Funding Information:
Gene and protein analysis. Human cDNA DKFZp686F1937 (BX648768) was used as the reference human sequence. This has sequence 5¢ to the National Center for Biotechnology Information (NCBI) reference clone of MKS3 (MGC26979) and results in a longer ORF. The structure of the mouse Mks3 mRNA is supported by RIKEN cDNA B230117007. We determined the sequence of rat Mks3 by amplification and sequencing of two RT-PCR products (951 bp and 2677 bp) from kidney (nucleotides 69 to 1019 and nucleotides 426 to 3102) and using the predicted rat cDNA. The predicted sequences of the chicken and fish (Tetraodon nigroviridis) meckelin in Supplementary Figure 1 online are based on those previously described but were modified comparing the human and rodent meckelin to each species’ genomic sequence to derive the most likely protein sequence. Sequence of the highly similar puffer fish, Fugu rubripes, was used for exon 3 of the fish sequence, as no T. nigroviridis
Funding Information:
We thank the MKS families for their generous help. We are grateful to M. Barr for useful discussions. This research was supported by grants from the Wellcome Trust to R.C.T. and E.R.M.; by grants to C.A.J. from the UK Birth Defects Foundation, University of Birmingham Medical School Scientific Projects and Birmingham Women’s Hospital Research Fund; and by grants from the US National Institutes of Health, the PKD Foundation and the Mayo Foundation to V.H.G. and to P.C.H.
PY - 2006/2
Y1 - 2006/2
N2 - 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 polydactyly1-3. 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.
AB - 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 polydactyly1-3. 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.
UR - https://www.scopus.com/pages/publications/31744441248
UR - https://www.scopus.com/pages/publications/31744441248#tab=citedBy
U2 - 10.1038/ng1713
DO - 10.1038/ng1713
M3 - Article
C2 - 16415887
AN - SCOPUS:31744441248
SN - 1061-4036
VL - 38
SP - 191
EP - 196
JO - Nature Genetics
JF - Nature Genetics
IS - 2
ER -