Alternative titles; symbols
HGNC Approved Gene Symbol: TMEM237
Cytogenetic location: 2q33.1 Genomic coordinates (GRCh38) : 2:201,620,186-201,643,503 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q33.1 | Joubert syndrome 14 | 614424 | Autosomal recessive | 3 |
TMEM237 is a tetraspanin protein localized to the ciliary transition zone that is predicted to function with other transition zone proteins in canonical and noncanonical Wnt (see 164820) signaling (Huang et al., 2011).
Huang et al. (2011) identified 2 TMEM237 splice variants that include either exon 1 or exon 2 and are translated into 2 different protein isoforms. Transcript-1 contains exon 1 and encodes a deduced 408-amino acid protein, designated isoform A, that has a long N-terminal domain, followed by 4 transmembrane domains and a short C-terminal tail. Both the N- and C-terminal domains are intracellular. The N-terminal domain and the intracellular loops between the transmembrane helices contain short repetitive motifs of basic (arg and/or lys) and acidic (asp and/or glu) residues that are highly conserved in metazoans. Immunocytochemical staining of polarized ciliated mouse inner medullary collecting duct (IMCD3) cells revealed that Tmem237 localized to the transition zone at the proximal region of primary cilia.
Zuniga and Craft (2010) cloned mouse Tmem237, which they called Als2cr4, and identified variants encoding 2 protein isoforms that differ only at the extreme N terminus. The deduced 403-amino acid protein encoded by Als2cr4 transcript-2 has a calculated molecular mass of about 45 kD and shares 81% and 82% identity with isoforms A and B of human ALS2CR4, respectively. Mouse Als2cr4 has a long N-terminal domain containing a tetratricopeptide motif, followed by 4 transmembrane segments and a short C-terminal tail. Zuniga and Craft (2010) noted that previous in situ hybridization and gene expression profiles revealed high Als2cr4 expression in eye, hippocampus, cerebellum, and olfactory bulb. By immunohistochemical analysis of retina, Zuniga and Craft (2010) found Als2cr4 enriched in retina and localized to photoreceptor outer segments, ciliary complex, and horizontal cells in the outer plexiform layer. Immunoelectron microscopy verified Als2cr4 expression in the discs of photoreceptor outer segments.
By yeast 2-hybrid analysis of mouse retina, Zuniga and Craft (2010) found that Als2cr4 interacted with Arr4 (ARR3; 301770). Immunoprecipitation analysis of light-adapted mouse retinas showed that Als2cr4 associated with cytoskeletal components. Als2cr4 interacted directly with myosin Va (MYO5A; 160777), myosin VI (MYO6; 600970), and Arr3.
Huang et al. (2011) found that knockdown of Tmem237 in IMCD3 cells via small interfering RNA impaired ciliogenesis and caused mislocalization of RhoA (165390) to peripheral regions of the basal body and to basolateral cell-cell contacts. Similarly, fibroblasts from a patient with Joubert syndrome-14 (JBTS14; 614424) and a null mutation in TMEM237 (R18X; 614423.0001) showed deregulation of canonical and noncanonical Wnt signaling and mislocalization of RHOA. Morpholino-mediated knockdown of Tmem237 in zebrafish caused gastrulation defects consistent with ciliary dysfunction that were similar to defects resulting from knockdown of other transition zone proteins, including Mks3 (TMEM67; 609884) and Tmem216 (613277). These defects in zebrafish were partially reversed by expression of human TMEM237, MKS3, or TMEM216. In both IMCD3 cells and C. elegans, transition zone localization of Tmem237 was dependent upon other transition zone proteins. Huang et al. (2011) hypothesized that TMEM237, TMEM216, and MKS3 function as a module to regulate ciliogenesis and WNT signaling.
Huang et al. (2011) determined that the TMEM237 gene contains 14 exons and spans 23 kb.
Zuniga and Craft (2010) stated that the human TMEM237 gene maps to chromosome 2q33.2 and that the mouse ortholog maps to chromosome 1.
By homozygosity mapping followed by candidate gene analysis in 10 related Canadian Hutterite families with Joubert syndrome-14 (JBTS14; 614424), Huang et al. (2011) identified a homozygous truncating mutation in the TMEM237 gene (R18X; 614423.0001). Homozygous or compound heterozygous mutations were also found in 3 additional families with the disorder (614423.0002-614423.0005). All the mutations were predicted to result in a null allele. Protein extracts from patient cells showed perturbation of the noncanonical WNT pathway, with constitutive phosphorylation and hyperactivation of DVL1 (601365) and an increase in CTNNB1 (116806) levels. There was also an increase in RHOA signaling. The phenotype was characterized by severe mental retardation, abnormal breathing pattern in infancy, molar tooth sign on brain imaging, renal cysts, abnormal eye movements, and early death in many patients.
In affected members of 10 related Canadian Hutterite families with Joubert syndrome-14 (JBTS14; 614424) (Boycott et al., 2007), Huang et al. (2011) identified a homozygous 52C-T transition in the TMEM237 gene, resulting in an arg18-to-ter (R18X) substitution. Screening of normal Hutterite controls showed a carrier frequency of 6% for this mutation. The mutation was not found in over 105 northern European controls. TMEM237 transcript levels were reduced by 99.6% in patient fibroblasts, and these cells showed defective ciliogenesis and pairing of centrioles compared to control cells.
Chong et al. (2012) identified a carrier frequency for this mutation of 0.080 (1 in 12.5) among Schmiedeleut (S-leut) Hutterites in the United States. This mutation is private to the Hutterite population.
In affected members of a consanguineous Austrian family with Joubert syndrome-14 (JBTS14; 614424) (Janecke et al., 2004), Huang et al. (2011) identified a homozygous G-to-T transversion in intron 9 of the TMEM237 gene (677+1G-T). RT-PCR analysis and sequencing of a patient's fibroblasts showed 2 aberrant transcripts: one resulting in the deletion of 65 amino acids and the insertion of a serine residue, and another resulting in the skipping of exon 9 and premature termination. TMEM237 transcript levels were reduced by 98.4% in patient fibroblasts, and these cells showed defective ciliogenesis and pairing of centrioles compared to control cells.
In a Jordanian child, born of consanguineous parents, with Joubert syndrome-14 (JBTS14; 614424), Huang et al. (2011) identified a homozygous 1-bp duplication (1066dupC) in exon 13 of the TMEM237 gene, predicted to result in a frameshift and premature termination. The mutation was not found in over 105 Jordanian controls.
In a child of European and Spanish descent with Joubert syndrome-14 (JBTS14; 614424), Huang et al. (2011) identified compound heterozygosity for 2 mutations in the TMEM237 gene: a maternally inherited 76C-T transition, resulting in a gln26-to-ter (Q26X) substitution, and a paternally inherited G-to-T transversion in intron 11 (943+1G-T; 614423.0005), resulting in an in-frame deletion of 56 amino acids (exons 11 and 12). The mutations were not found in over 105 controls.
For discussion of the splice site mutation in the TMEM237 gene (943+1G-T) that was found in compound heterozygous state in a patient with Joubert syndrome-14 (JBTS14; 614424) by Huang et al. (2011), see 614423.0004.
Boycott, K. M., Parboosingh, J. S., Scott, J. N., McLeod, D. R., Greenberg, C. R., Fujiwara, T. M., Mah, J. K., Midgley, J., Wade, A., Bernier, F. P., Chodirker, B. N., Bunge, M., Innes, A. M. Meckel syndrome in the Hutterite population is actually a Joubert-related cerebello-oculo-renal syndrome. Am. J. Med. Genet. 143A: 1715-1725, 2007. [PubMed: 17603801] [Full Text: https://doi.org/10.1002/ajmg.a.31832]
Chong, J. X., Ouwenga, R., Anderson, R. L., Waggoner, D. J., Ober, C. A population-based study of autosomal-recessive disease-causing mutations in a founder population. Am. J. Hum. Genet. 91: 608-620, 2012. [PubMed: 22981120] [Full Text: https://doi.org/10.1016/j.ajhg.2012.08.007]
Huang, L., Szymanska, K., Jensen, V. L., Janecke, A. R., Innes, A. M., Davis, E. E., Frosk, P., Li, C., Willer, J. R., Chodirker, B. N., Greenberg, C. R., McLeod, D. R., and 31 others. TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone. Am. J. Hum. Genet. 89: 713-730, 2011. [PubMed: 22152675] [Full Text: https://doi.org/10.1016/j.ajhg.2011.11.005]
Janecke, A. R., Muller, T., Gassner, I., Kreczy, A., Schmid, E., Kronenberg, F., Utermann, B., Utermann, G. Joubert-like syndrome unlinked to known candidate loci. J. Pediat. 144: 264-269, 2004. [PubMed: 14760273] [Full Text: https://doi.org/10.1016/j.jpeds.2003.11.010]
Zuniga, F. I., Craft, C. M. Deciphering the structure and function of Als2cr4 in the mouse retina. Invest. Ophthal. Vis. Sci. 51: 4407-4415, 2010. [PubMed: 20375344] [Full Text: https://doi.org/10.1167/iovs.10-5251]