TMEM138 encodes a member of the tetraspanin family of mulit-pass transmembrane proteins. Among various protein networks in primary cilia, proteins of the tectonic complex were found to partly play a role in transporting intracellular vesicles to the cilium. TMEM138 is thought to function as part of this complex by marking post-Golgi vesicles that carry ciliary proteins. TMEM138-tagged vesicles and other transmembrane tagged vesicles are tethered in transport to the base of the cilium, a requirement for ciliary assembly and function. Dysfunctional ciliary genes result in various ciliopathies that arise due to absent or underdeveloped cilia.
TMEM138 dysfunction results in autosomal recessive Joubert Syndrome 16 (JBTS16), a neurodevelopmental and multi-visceral disorder characterized by the Molar Tooth Sign (MTS), a mid-hindbrain malformation easily identifiable through an axial brain MRI scan.
TMEM138 is located on the q arm of chromosome 11, it is 14,502 bases long ranging from 61,362,001 to 61,376,502 pter. It contains 5 exons and translates into a 162aa long protein with a molecular weight of 19,262 Da. TMEM138 is expressed ubiquitously in the cytoplasm and is most abundant in cilia; it is most expressed in the retina. Three alternatively spliced isoforms have been identified. TMEM138 is aligned with TMEM216 in a head to tail configuration; both genes flank a conserved regulatory element in the intergenic region, responsible for co-regulating their expression. TMEM138 and TMEM216 are thought to be involved in marking relatively distinct post-Golgi vesicles that carry essential ciliary proteins. This tagging is required for ciliary assembly.
Homozygous mutations in TMEM138 result in Joubert Syndrome 16. The first screening for pathogenic TMEM138 variants reported 5 unique recurring mutations, including 1 splice site and 4 missense mutations, mainly identified in Arab and Pakistani families.
See United Arab Emirates > [Lee et al., 2012]
Lee et al., (2012) identified TMEM138 as a ciliary gene associated with JS (JBTS16) and performed the first mutation screening in a large group of JS cases who tested negative for mutations in previously suspected genes. 17 individuals from 3 Emirati families, 1 Omani family, and 2 Egyptian families were reported. Two children from one Emirati family harbored an intronic splice site transition mutation (c.128+5G>A); three children from the second Emirati family exhibited the same intronic mutation. In the third Emirati family, 3 adults were found to harbor a missense transition mutation (c.380C>T; p.Ala127Val). In the Omani family, 1 infant was found to harbor a different missense transition (c.389A>G; p.Tyr130Cys); 6 siblings are deceased. Lastly, a third missense transition (c.376G>A; p.Ala126Thr) was identified in 1 infant and 1 child, each from separate Egyptian families. All mutations were reported to occur at evolutionarily conserved positions.
Ben-Salem et al., (2014) reviewed the mutation spectrum for Joubert Syndrome in the Arab world. Among the cases, 3 individuals from 2 Emirati families were diagnosed with JBTS16. The Individuals harbored the same missense transversion mutation in TMEM138 (c.389A>G; p.Tyr130Cys) that was described by Lee et al. (2012).
Bizzari S et al., (2017) reported on two Emirati siblings who were diagnosed with Joubert Syndrome 16 (JBTS16). Whole Exome Sequencing identified a previously identified splice site transition mutation in TMEM138 (c.128+5 G>A). The mutation occurred at a conserved residue 5 nucleotides downstream of the second intron. In silico splice site prediction algorithms indicate that this mutation abolished the wild type donor site at intron 2; a stop codon was identified 6 nucleotides downstream of the mutation indicating protein truncation. His unaffected consanguineous parents (1st cousins once removed) are carriers of this mutation.
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