HGNC Approved Gene Symbol: TMEM231
Cytogenetic location: 16q23.1 Genomic coordinates (GRCh38) : 16:75,536,741-75,556,286 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q23.1 | Joubert syndrome 20 | 614970 | Autosomal recessive | 3 |
| Meckel syndrome 11 | 615397 | Autosomal recessive | 3 |
TMEM231 is a critical component of a protein complex in the basal body, a ring-like structure that functions in the transition zone at the base of cilia. This complex acts as a barrier to restrict protein diffusion between plasma and ciliary membranes (Chih et al., 2012).
Chih et al. (2012) cloned mouse Tmem231, which encodes a deduced 315-amino acid protein with both N-terminal and C-terminal transmembrane domains. Tmem231 localized to the base of cilia in mouse IMCD3 cells and embryonic fibroblasts. Database analysis revealed no orthologs of Tmem231 in C. elegans or Drosophila.
Using tandem affinity purification and mass spectrometry, Chih et al. (2012) identified Tmem231 as a component of a high molecular mass B9d1-containing ciliary complex in mouse cells. Besides B9d1 and Tmem231, other proteins detected within this complex included Tmem17 (614950), B9d2 (611951), Tctn1 (609863), Tctn2 (613846), Mks1 (609883), Ahi1 (608894), Cc2d2a (612013), and Kctd10 (613421). Knockdown of B9d1, Tmem231, Tmem17, or Cc2d2a via small interfering RNA had a modest effect on cilia formation, but significantly reduced the amount of the somatostatin receptor Sstr3 (182453) that localized to cilia. Knockdown of B9d1, Tmem231, Tmem17, or Cc2d2a also interfered with sonic hedgehog signaling (see SHH, 600725) by preventing the movement of Smo (SMOH; 601500) into the ciliary membrane. Knockout of B9d1 and Tmem231 resulted in delayed ciliogenesis and cilia growth due to absence of diffusion barrier formation. Chih et al. (2012) concluded that formation of a diffusion barrier by the B9d1 complex is required for the formation and retention of cilia components.
Hartz (2012) mapped the TMEM231 gene to chromosome 16q23.1 based on an alignment of the TMEM231 sequence (GenBank AK057689) with the genomic sequence (GRCh37).
Joubert Syndrome 20
In 3 patients from 2 French Canadian families with Joubert syndrome-20, (JBTS20; 614970), Srour et al. (2012) identified compound heterozygosity for 2 mutations in the TMEM231 gene (614949.0001 and 614949.0002). The mutations were identified by exome sequencing and confirmed by Sanger sequencing.
Meckel Syndrome, Type 11
In a patient, born of consanguineous Arab parents, with Meckel syndrome type 11 (MKS11; 615397), Shaheen et al. (2013) identified a homozygous mutation in the TMEM231 gene (614949.0003). An unrelated Arab patient with the disorder carried a different homozygous mutation (614949.0004). The findings indicated that TMEM231 mutations can cause variable ciliopathy phenotypes.
Chih et al. (2012) found that knockout of B9d1 or Tmem231 in mice led to lethality around embryonic day 15.5 with severe vascular defects. The phenotypes of B9d1 -/- and Tmem231 -/- mice were indistinguishable and showed signs of disrupted Shh signaling, including microphthalmia and polydactyly, and defects in patterning of the ventral spinal cord, consistent with a ciliopathy. Both B9d1 -/- and Tmem231 -/- embryos showed loss of cilia and altered Shh gene expression, including absence of Shh-positive floorplate cells.
In 3 patients from 2 French Canadian families with Joubert syndrome-20 (JBTS20; 614970), Srour et al. (2012) identified compound heterozygosity for 2 mutations in the TMEM231 gene: a 12T-A transversion in exon 1, resulting in a tyr4-to-ter (Y4X) substitution, and a 625G-A transition resulting in an asp209-to-asn (D209N; 614949.0002) substitution at a highly conserved residue. The Y4X leads to a nonsense mutation in the canonical isoform and 2 other predicted isoforms of TMEM231, whereas it abolishes the translation initiation methionine in a longer isoform. The D209N variant was seen in 1 of 416 French Canadian controls and in 0.01% of several large databases. Each unaffected parent was heterozygous for 1 of the mutations. Haplotype analysis of both variants suggested a founder effect.
For discussion of the asp209-to-asn (D209N) mutation in the TMEM231 gene that was found in compound heterozygous state in patients with Joubert syndrome-20 (JBTS20; 614970) by Srour et al. (2012), see 614949.0001.
In a patient, born of consanguineous Arab parents, with Meckel syndrome type 11 (MKS11; 615397), Shaheen et al. (2013) identified a homozygous c.751G-A transition in the last nucleotide of exon 4 of the TMEM231 gene. The mutation was found by exome sequencing of the proband and was not found in several large control databases. Analysis of lymphoblastoid cell lines from the unaffected parents showed that the mutation resulted in a splicing defect and 2 aberrant TMEM231 transcripts: 1 that retained 47 bp from intron 4 (10%) and another that retained 11 bp from intron 4 (5%). Both aberrant transcripts were predicted to result in a frameshift and premature termination (Val251SerfsTer21 and Val251SerfsTer9, respectively). Further analysis indicated that the mutation resulted in nonsense-mediated mRNA decay. Meckel syndrome was diagnosed prenatally by the presence of oligohydramnios, occipital encephalocele, polydactyly, and polycystic kidneys. Therapeutic termination was performed; a previous fetus was similarly affected.
In an Arab patient with Meckel syndrome type 11 (MKS11; 615397), Shaheen et al. (2013) identified a homozygous c.902A-C transversion in the TMEM231 gene, resulting in a gln301-to-pro (Q301P) substitution at a highly conserved residue. The mutation was not found in 200 control Saudi exomes. Functional studies of the variant were not performed.
Chih, B., Liu, P., Chinn, Y., Chalouni, C., Komuves, L. G., Hass, P. E., Sandoval, W., Peterson, A. S. A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain. Nature Cell Biol. 14: 61-72, 2012. [PubMed: 22179047] [Full Text: https://doi.org/10.1038/ncb2410]
Hartz, P. A. Personal Communication. Baltimore, Md. 11/27/2012.
Shaheen, R., Ansari, S., Al Mardawi, E., Alshammari, M. J., Alkuraya, F. S. Mutations in TMEM231 cause Meckel-Gruber syndrome. J. Med. Genet. 50: 160-162, 2013. [PubMed: 23349226] [Full Text: https://doi.org/10.1136/jmedgenet-2012-101431]
Srour, M., Hamdan, F. F., Schwartzentruber, J. A., Patry, L., Ospina, L. H., Shevell, M. I., Desilets, V., Dobrzeniecka, S., Mathonnet, G., Lemyre, E., Massicotte, C., Labuda, D., Amrom, D., Andermann, E., Sebire, G., Maranda, B., FORGE Canada Consortium, Rouleau, G. A., Majewski, J., Michaud, J. L. Mutations in TMEM231 cause Joubert syndrome in French Canadians. J. Med. Genet. 49: 636-641, 2012. [PubMed: 23012439] [Full Text: https://doi.org/10.1136/jmedgenet-2012-101132]