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

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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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Figure 1: Refinement of the MKS3 gene locus by haplotype analysis in the consanguineous pedigrees 29A and 33A, 67F, 40T and 125.
Figure 2: Identification the MKS3 gene by direct mutational analysis of positional candidates.
Figure 3: Genetic and physical mapping of the Wpk gene.
Figure 4: RNA blot and real-time PCR analyses of MKS3 expression.

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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.

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Correspondence to Peter C Harris or Colin A Johnson.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Sequence alignment of meckelin proteins from human, rat, mouse, chicken and Tetraodon nigroviridis. (PDF 1360 kb)

Supplementary Table 1

Intron/exon structure of MKS3/TMEM67 and Mks3/Tmem67. (PDF 99 kb)

Supplementary Table 2

Novel human chromosome 8 microsatellite markers for the MKS3 locus and novel rat chromosme 5 microsatellite markers for the Wpk locus. (PDF 86 kb)

Supplementary Table 3

Sequencing primers for the MKS3/TMEM67 gene. (PDF 75 kb)

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