9.B.77 The Meckel Syndrome Protein (Meckelin) Family 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. MKS is genetically heterogeneous, with three loci mapped: MKS1, 17q21-24; MKS2, 11q13 and MKS3. MKS3 is syntenic to the Wpk locus in rat, which is a model for polycystic kidney disease, agenesis of the corpus callosum and hydrocephalus. Positional cloning of the Wpk gene suggested a MKS3 candidate gene, TMEM67, for which pathogenic mutations for five MKS3-linked consanguineous families have been identified (Smith et al., 2006). 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 protein of unknown function (Smith et al., 2006). MKS3 domains show sequence similarity to zinc finger domains, insect antifreeze domains, neurohypophysial hormones, Bowman-Birk serine proteases, and Leishmanolysin family proteins. These proteins are found in eukaryotes and may prove to be receptors. Their topology resembles one-half of RND transporters.
References:
Dawe, H.R., U.M. Smith, A.R. Cullinane, D. Gerrelli, P. Cox, J.L. Badano, S. Blair-Reid, N. Sriram, N. Katsanis, T. Attie-Bitach, S.C. Afford, A.J. Copp, D.A. Kelly, K. Gull, and C.A. Johnson. (2007). The Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation. Hum Mol Genet 16: 173-186.
Smith U.M., M. Consugar, L.J. Tee, B.M. McKee, E.N. Maina, S. Whelan, N.V. Morgan, E. Goranson, P. Gissen, S. Lilliquist, I.A. Aligianis, C.J. Ward, S. Pasha, R. Punyashthiti, S. Malik Sharif, P.A. Batman, C.P. Bennett, C.G. Woods, C. McKeown, M. Bucourt, C.A. Miller, P. Cox, L. Algazali,R.C. Trembath, V.E. Torres, T. Attie-Bitach, D.A. Kelly, E.R. Maher, V.H. Gattone 2nd, P.C. Harris, C.A. Johnson. (2006). The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat. Nat. Genet. 38: 191-196.
Tkemaladze, T., G. Melikishvili, V. Kherkheulidze, A. Melikishvili, and T. Davitaia. (2017). EXPANDED PHENOTYPE OF TMEM67 GENE MUTATION (CASE REPORT). Georgian Med News 100-103.
Examples:
TC#	Name	Organismal Type	Example
9.B.77.1.1	The Meckel (Meckel-Gruber) syndrome type 3 protein (Meckelin, TMEM67, MKS3) (995 aas; 7 TMSs in a 1+5+1 arrangement). Human ciliopathies are in a class of multi-organ genetic disorders caused by defects in proteins expressed at the primary cilium, an organelle present on the cell surface of many cell types (Dawe et al. 2007). Dozens of causative genes for ciliopathies have been identified, and many of them are known to cause allelic disease. The TMEM67 gene in mutant form is known to be associated with a broad range of clinical presentations, namely Joubert syndrome 6 (JBTS6), nephronophthisis 11 (NPHP11), Bardet-Biedel syndrome (BBS), COACH syndrome, and lethal Meckel syndrome type 3 (MKS3) (Tkemaladze et al. 2017). It is required for ciliary structure and function as part of the tectonic-like complex (TC# 8.A.170.1.1) which is required for tissue-specific ciliogenesis; it may regulate ciliary membrane composition.	Animals	Meckelin of Homo sapiens (Q5HYA8)

9.B.77.1.2	Mechelin of 738 aas and at least 5 TMSs in a 1 + 2 + 2 TMS arrangement.		Mechelin of Tetrabaena socialis

9.B.77.1.3	Meckelin of 669 aas and 5 TMSs in a 3 + 2 TMS arrangement.		Meckelin of Eumeta japonica

9.B.77.1.4	Uncharacterized protein of 285 aas and 1 N-terminal TMS. (may be a fragment lacking the C-terminal membrane-embedded part of its homologues.		UP of Haemonchus placei

9.B.77.1.5	Uncharacterized protein of 427 aas, possibly with 4 TMSs in a 3 + 1 TMS arrangement.		UP of Rhizoclosmatium globosum

9.B.77.1.6	Uncharacterized protein of 473 aas and 1 N-terminal TMS plus other potential putative TMSs.		UP of Trypanosoma cruzi