Transmembrane protein 67 (TMEM67), also known as Meckelin, encodes ciliary protein. It is likely implicated as a membrane receptor involved in signaling events during development and plays, with MKS1 gene, important roles in ciliogenesis, TMEM67 is most likely required for normal ciliary sensory signaling.
TMEM67 gene is located on the long arm of chromosome 8 at 8q21.13-q22.1 and its coding sequence consists of 28 exons. The TMEM67 protein is 995 amino acids long and it has an unglycosylated weight of 108 KDa. It is expressed in all adult and fetal tissue with higher expression in embryonic adrenal gland, brain, kidney, lung and spinal cord. It localizes to primary cilia of the epithelial cells. Meckelin was predicted to contain a signal peptide, at least two cysteine-rich repeats, and a 490-residue extracellular region with four N-linked glycosylated sites, followed by seven transmembrane domains and a 30-residue cytoplasmic tail.
Mutations in the TMEM67 gene cause Meckel syndrome type 3. In addition, it was also identified that mutations in the TMEM67 gene occurred in patients affected with Joubert syndrome (JS), thus leading to define this gene as a sixth JS locus (JBTS6).
Khaddour et al. (2007) identified a novel polymorphism (c.507-19T>C) in intron 4 of the MKS3 gene in a Lebanese case with Meckel syndrome.
Khaddour et al. (2007) identified a novel polymorphism (c.1575+53G>A) in intron 15 of the MKS3 gene in a Mauritanian case with Meckel syndrome.
A Meckel syndrome case from non-consanguineous family originating from Morocco was found to be compound heterozygotes for MKS3 mutations by Khaddour et al. (2007). This case was found to carry the missense mutation c.1336G>C (p.D446H) in exon 13 of the MKS3 and a c.2439G>A mutation located at the last base of exon 23 that, although it did not change the amino acid (p.A813A), abolished the donor splice site following in silico analysis. In addition to that, Khaddour et al. (2007) identified a novel polymorphism, c.2952A>G (A984A), in exon 28 of the MKS3 gene in a Moroccan patient.
[See: United Arab Emirates > Smith et al., 2006].
Khaddour et al. (2007) identified a homozygous splice site mutation, c.1065+1delG, in exon 10 of the MKS3 gene. This mutation was found in homozygous state in a Meckel syndrome case from a consanguineous family originating from Palestine.
Shaheen et al. (2013) recruited MKS affected patients from 18 consanguineous Saudi families to determine the causal gene defects. DNA was obtained from both affected and healthy members of these families and an autozygome guided mutation analysis of known MKS genes was undertaken. This approach resulted in the identification of a homozygous c.2306delT mutation in the TMEM67 gene resulting in p.Leu769Tyrfs4 in one of the affected families.
Al-Hamed et al. (2016) researched the underlying gene defects in a cohort of 44 Saudi families affected by antenatal cystic kidney disease. Genetic screening of 90 renal genes found TMEM67 mutations in two consanguineous families. In the first case, the fetus showed enlarged echogenic kidneys with cysts, oligohydramnios/anhydramnios and growth malformations such as a narrow thorax and dolichocephaly. The case resulted in fetal death. The fetus was found to be homozygous for the novel TMEM67 mutation c. 457T>G (p.C153G). In the second family, antenatal ultrasound of the proband found enlarged cystic kidneys, oligohydramnios/anhydramnios, cerebellar vermis aplasia, hydrocephalus, congenital heart malformation and pericardial effusion. This case also resulted in fetal death. The proband had two similarly affected siblings and was homozygous for the novel splice site mutation c.1413-2A>G, which was found to result in a broken acceptor site.
Khaddour et al. (2007) identified a novel polymorphism, c.1665-109_1665-108insT, in intron 16 of the MKS3 gene in a Tunisian case with Meckel syndrome.
In an attempt to determine the gene mutant in Meckel syndrome type 3, Smith et al. (2006) refined mapping of the phenotype of five consanguineous families, including an Emirati family of Omani origin, to a 12.67-Mb interval on chromosome 8q21.13-q22.1 with synteny to the Wpk locus in rat, which is a model with polycystic kidney disease, agenesis of the corpus callosum and hydrocephalus. Positional cloning of the Wpk gene suggested a MKS3 candidate gene, TMEM67, for which Smith et al. (2006) identified pathogenic mutations in the five MKS3-linked consanguineous families. In an individual with Meckel syndrome type 3 from Oman, Smith et al. (2006) found a homozygous 2-bp deletion in exon 3 of the MKS3 gene, 383-384delAC, causing a frameshift beginning at his128 with premature stop at residue 140 (H128fsX140). Each of the first-cousin parents was heterozygous for the mutation. This mutation was not detected in more than 120 ethnically matched normal control chromosomes, suggesting that it is not common polymorphism. The affected individual had occipital encephalocele, Dandy-Walker cysts, renal cystic dysplasia, hepatic developmental defects, and left-hand postaxial polydactyly.
To contribute with your findings to the content of this record, please fill the CTGA Database Information Submission Form and email it, along with supportive documents, to firstname.lastname@example.org.