HGNC Approved Gene Symbol: TMEM138
Cytogenetic location: 11q12.2 Genomic coordinates (GRCh38) : 11:61,362,374-61,376,870 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q12.2 | Joubert syndrome 16 | 614465 | Autosomal recessive | 3 |
TMEM138 is required for the assembly and function of cilia (Lee et al., 2012).
Lee et al. (2012) identified the TMEM138 gene near the TMEM216 (613277) gene in a region of chromosome 11 linked to Joubert syndrome-2 (JBTS2; 608091). They obtained TMEM138 clones, including potential variants, from a human fetal brain cDNA library. The deduced major isoform of TMEM138 contains 162 amino acids and has an N-terminal signal sequence followed by 3 transmembrane domains. Expression profiling showed TMEM138 expression in all tissues examined. In situ hybridization of human embryos at 4 to 8 weeks' gestation revealed ubiquitous TMEM138 expression that increased with time. TMEM138 expression appeared to parallel TMEM216 expression in all tissues examined. Immunohistochemical analysis of mouse IMCD3 cells and transfected COS-7 cells revealed that Tmem138 localized to ciliary axoneme/basal body and that Tmem216 localized to basal body and to the Golgi apparatus surrounding the base of cilium. The 2 proteins also appeared to localize to different vesicle pools that moved toward the primary cilia over time. Tmem138 vesicles, but not Tmem216 vesicles, colocalized with endogenous Cep290 (610142) in IMCD3 cells.
Lee et al. (2012) determined that the TMEM138 gene contains 5 exons, the first of which is noncoding. The 23-kb intergenic region between TMEM138 and TMEM216 contains a functional conserved RFX4 (603958)-binding site.
By genomic sequence analysis, Lee et al. (2012) mapped the TMEM138 gene to chromosome 11q12.2, 23 kb from the TMEM216 gene. TMEM138 and TMEM216 are in a head-to-tail orientation.
Lee et al. (2012) mapped the mouse Tmem138 gene to a region of chromosome 19 that shares homology of synteny with human chromosome 11q12.2.
Lee et al. (2012) found that RFX4 mediated coordinated expression of TMEM138 and TMEM216 by binding to a regulatory element within their intergenic region. Knockdown of either Tmem138 or Tmem216 in mouse IMCD3 cells resulted in short cilia and a defect in ciliogenesis. Knockdown of Tmem216 disrupted vesicular trafficking of Tmem138 and Cep290, whereas knockdown of Tmem138 had little effect on vesicular movement of Tmem216. Knockdown of Trappc9 (611966), a component of the transport protein particle (TRAPP) II complex, disrupted vesicular tethering of both proteins and reduced ciliogenesis.
Lee et al. (2012) found that the TMEM138 and TMEM216 genes are aligned in a head-to-tail orientation, with a conserved intergenic region, in higher vertebrates only. They determined that the 2 genes came into close association during an ancient chromosomal rearrangement at the amphibian-to-reptile transition about 340 million years ago. Conservation in the intergenic region becomes progressively weaker from human to anolis lizard, and the orthologous genes map to different chromosomes in zebrafish.
By repeat sequencing of candidate genes in 6 consanguineous Arab families with Joubert syndrome showing linkage to the JBTS2 locus (608091) on chromosome 11q13, but who were negative for mutations in the TMEM216 gene (613277), Lee et al. (2012) identified homozygous mutations in the TMEM138 gene (614459.0001-614459.0005). None of the mutations was found in 400 controls. Two additional patients from consanguineous Arab families were also found to carry homozygous TMEM138 mutations. The phenotype included the molar tooth sign on brain imaging, oculomotor apraxia, variable coloboma, and rare kidney involvement. The phenotype was indistinguishable from that caused by mutation in TMEM216 gene.
Associations Pending Confirmation
By examining 1,570 ethnically diverse African genomes from individuals with quantified pigmentation levels, Crawford et al. (2017) identified 33 SNPs, predicted to be causal for skin pigmentation, in an approximately 195-kb region of chromosome 11 that includes genes that play a role in ultraviolet response and melanoma risk. The region included the DDB1 (600045) and TMEM138 genes. The most significantly associated SNP in the DDB1/TMEM138 region was rs7948623 (p = 2.2 x 10(-11)), located 172 bp downstream of TMEM138. Constructs containing rs7948623 showed enhancer activity in a human melanoma cell line and interacted with the promoters of DDB1 and neighboring genes in a human breast adenocarcinoma cell line. The derived rs7948623T allele, associated with dark pigmentation, is most common in East African Nilo-Saharan populations and is at moderate to high frequency in South Asian and Australo-Melanesian populations. At SNP rs11230664, an intronic SNP within DDB1, the ancestral C allele, associated with dark pigmentation, is common in all sub-Saharan African populations, having the highest frequency in East African Nilo-Saharan, Hadza, and San populations (88 to 96%) and is at moderate to high frequency in South Asian and Australo-Melanesian populations (12 to 66%). The derived T allele, associated with light pigmentation, is nearly fixed in European, East Asian, and Native American populations. The times to the most recent common ancestor (TMRCAs) for the derived alleles rs7948623T and rs11230664T were estimated to be older than 600,000 and 250,000 years, respectively. RNA-seq data from 106 primary melanocyte cultures indicated that African ancestry is correlated with increased DDB1 gene expression (p = 2.6 x 10(-5)), and the ancestral rs7120594T allele, associated with dark pigmentation, was correlated with increased DDB1 expression. Variants associated with dark pigmentation in Africans were found to be identical by descent in South Asian and Australo-Melanesian populations.
Lee et al. (2012) found that knockdown of zebrafish Tmem138 or Tmem216 resulted in similar, but distinct, phenotypes. Knockdown of either gene resulted in pericardial effusion, curved or kinked tail, and gastrulation defects. However, only knockdown of Tmem16 resulted in hydrocephalic brains.
In affected members of 2 consanguineous Arab families with Joubert syndrome-16 (JBTS16; 614465), Lee et al. (2012) identified a homozygous G-to-A transition in exon 2 of the TMEM138 gene, resulting in a splice site mutation at a highly conserved position. Features were somewhat variable, but included the molar tooth sign on brain imaging, oculomotor apraxia, and coloboma. One patient had cystic kidneys and another had polydactyly.
In 2 Arab sibs, born of consanguineous parents, with Joubert syndrome (JBTS16; 614465), Lee et al. (2012) identified a homozygous 287A-G transition in the TMEM138 gene, resulting in a his96-to-arg (H96R) substitution in a highly conserved residue. A 17-year-old boy had the molar tooth sign and a Dandy-Walker malformation, oculomotor apraxia, and nephronophthisis. An affected fetus had an encephalocele and was diagnosed with Meckel syndrome. In vitro functional expression studies showed that the mutant H96R protein was expressed at about 40% of control levels, suggesting a loss of function as the disease mechanism.
In 3 Arab sibs, born of consanguineous parents, with Joubert syndrome (JBTS16; 614465), Lee et al. (2012) identified a homozygous 380C-T transition in the TMEM138 gene, resulting in an ala127-to-val (A127V) substitution in a highly conserved residue. The patients had the molar tooth sign and retinal dystrophy.
In 3 patients from 3 consanguineous Arab families with Joubert syndrome (JBTS16; 614465), Lee et al. (2012) identified a homozygous 376G-A transition in the TMEM138 gene, resulting in an ala126-to-thr (A126T) substitution in a highly conserved residue. All patients had the molar tooth sign and oculomotor apraxia, and 2 had coloboma.
In a patient, born of consanguineous Arab parents, with Joubert syndrome (JBTS16; 614465), Lee et al. (2012) identified a homozygous 389A-G transition in the TMEM138 gene, resulting in a tyr130-to-cys (Y130C) substitution in a highly conserved residue. The patient had the molar tooth sign, oculomotor apraxia, coloboma, and cystic kidneys. Six deceased sibs were reportedly affected.
Crawford, N. G., Kelly, D. E., Hansen, M. E. B., Beltrame, M. H., Fan, S., Bowman, S. L., Jewett, E., Ranciaro, A., Thompson, S., Lo, Y., Pfeifer, S. P., Jensen, J. D., and 36 others. Loci associated with skin pigmentation identified in African populations. Science 358: eaan8433, 2017. Note: Electronic Article. Erratum: Science 367: eaba7178, 2020. [PubMed: 29025994] [Full Text: https://doi.org/10.1126/science.aan8433]
Lee, J. H., Silhavy, J. L., Lee, J. E., Al-Gazali, L., Thomas, S., Davis, E. E., Bielas, S. L., Hill, K. J., Iannicelli, M., Brancati, F., Gabriel, S. B., Russ, C., and 18 others. Evolutionarily assembled cis-regulatory module at a human ciliopathy locus. Science 335: 966-969, 2012. [PubMed: 22282472] [Full Text: https://doi.org/10.1126/science.1213506]