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

Ursula M. Smith; Mark Consugar; Louise J. Tee; Brandy M. McKee; Esther N. Maina; Shelly Whelan; Neil V. Morgan; Erin Goranson; Paul Gissen; Stacie Lilliquist; Irene A. Aligianis; Christopher J. Ward; Shanaz Pasha; Rachaneekorn Punyashthiti; Saghira Malik Sharif; Philip A. Batman; Christopher P. Bennett; C. Geoffrey Woods; Carole McKeown; Martine Bucourt; Caroline A. Miller; Phillip Cox; Lihadh AlGazali; Richard C. Trembath; Vicente E. Torres; Tania Attie-Bitach; Deirdre A. Kelly; Eamonn R. Maher; Vincent H. Gattone; Peter C. Harris; Colin A. Johnson

doi:10.1038/ng1713

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

Ursula M. Smith, Mark Consugar, Louise J. Tee, Brandy M. McKee, Esther N. Maina, Shelly Whelan, Neil V. Morgan, Erin Goranson, Paul Gissen, Stacie Lilliquist, Irene A. Aligianis, Christopher J. Ward, Shanaz Pasha, Rachaneekorn Punyashthiti, Saghira Malik Sharif, Philip A. Batman, Christopher P. Bennett, C. Geoffrey Woods, Carole McKeown, Martine BucourtCaroline A. Miller, Phillip Cox, Lihadh AlGazali, Richard C. Trembath, Vicente E. Torres, Tania Attie-Bitach, Deirdre A. Kelly, Eamonn R. Maher, Vincent H. Gattone, Peter C. Harris, Colin A. Johnson

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Abstract

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^1-3. 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.

Original language	English
Pages (from-to)	191-196
Number of pages	6
Journal	Nature Genetics
Volume	38
Issue number	2
DOIs	https://doi.org/10.1038/ng1713
Publication status	Published - Feb 2006

ASJC Scopus subject areas

Genetics

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Smith, U. M., Consugar, M., Tee, L. J., McKee, B. M., Maina, E. N., Whelan, S., Morgan, N. V., Goranson, E., Gissen, P., Lilliquist, S., Aligianis, I. A., Ward, C. J., Pasha, S., Punyashthiti, R., Sharif, S. M., Batman, P. A., Bennett, C. P., Woods, C. G., McKeown, C., ... Johnson, C. A. (2006). The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat. Nature Genetics, 38(2), 191-196. https://doi.org/10.1038/ng1713

Smith, UM, Consugar, M, Tee, LJ, McKee, BM, Maina, EN, Whelan, S, Morgan, NV, Goranson, E, Gissen, P, Lilliquist, S, Aligianis, IA, Ward, CJ, Pasha, S, Punyashthiti, R, Sharif, SM, Batman, PA, Bennett, CP, Woods, CG, McKeown, C, Bucourt, M, Miller, CA, Cox, P, AlGazali, L, Trembath, RC, Torres, VE, Attie-Bitach, T, Kelly, DA, Maher, ER, Gattone, VH, Harris, PC & Johnson, CA 2006, 'The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat', Nature Genetics, vol. 38, no. 2, pp. 191-196. https://doi.org/10.1038/ng1713

@article{bfc4d52148674a3899687c8c8a623b9c,

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

abstract = "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.",

author = "Smith, {Ursula M.} and Mark Consugar and Tee, {Louise J.} and McKee, {Brandy M.} and Maina, {Esther N.} and Shelly Whelan and Morgan, {Neil V.} and Erin Goranson and Paul Gissen and Stacie Lilliquist and Aligianis, {Irene A.} and Ward, {Christopher J.} and Shanaz Pasha and Rachaneekorn Punyashthiti and Sharif, {Saghira Malik} and Batman, {Philip A.} and Bennett, {Christopher P.} and Woods, {C. Geoffrey} and Carole McKeown and Martine Bucourt and Miller, {Caroline A.} and Phillip Cox and Lihadh AlGazali and Trembath, {Richard C.} and Torres, {Vicente E.} and Tania Attie-Bitach and Kelly, {Deirdre A.} and Maher, {Eamonn R.} and Gattone, {Vincent H.} and Harris, {Peter C.} and Johnson, {Colin A.}",

note = "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{\textquoteright} 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{\textquoteright}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.",

year = "2006",

month = feb,

doi = "10.1038/ng1713",

language = "English",

volume = "38",

pages = "191--196",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "2",

}

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.

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

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