Alternative titles; symbols
HGNC Approved Gene Symbol: TMEM107
Cytogenetic location: 17p13.1 Genomic coordinates (GRCh38): 17:8,172,457-8,176,380 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p13.1 | ?Joubert syndrome 29 | 617562 | Autosomal recessive | 3 |
| Meckel syndrome 13 | 617562 | Autosomal recessive | 3 | |
| Orofaciodigital syndrome XVI | 617563 | Autosomal recessive | 3 |
The TMEM107 gene encodes a protein that localizes to the transition zone (TZ) at the proximal region of the ciliary axoneme. The TZ regulates ciliary composition and signaling by facilitating a protein diffusion barrier at the ciliary base (summary by Lambacher et al., 2016).
Cilia are dynamic signaling organelles essential for developmental patterning, including left-right specification, skeletal formation, neural development, and organogenesis. TMEM107 is predicted to be critical for cilia formation and signaling in a subset of embryonic tissues (Christopher et al., 2012).
Christopher et al. (2012) reported that mouse and human TMEM107 contain 140 and 139 amino acids, respectively. Both have 4 transmembrane domains. TMEM107 orthologs are present in several species, including invertebrates. RT-PCR analysis detected Tmem107 expression in adult mouse liver, kidney, lung, eye, and brain, and in embryonic mouse limb, liver, and lung.
Shylo et al. (2016) found that TMEM107 localized to the proximal region of the ciliary axoneme, but not to the distal region of the cilia. TMEM107 was enriched in a region just distal to the basal body, suggesting that it may function within the TZ. TMEM107 colocalized with other TZ proteins, consistent with a role in regulating ciliary protein composition.
Hartz (2015) mapped the TMEM107 gene to chromosome 17p13.1 based on an alignment of the TMEM107 sequence (GenBank BC006292) with the genomic sequence (GRCh38).
Christopher et al. (2012) mapped the mouse Tmem107 gene to chromosome 11.
Meckel Syndrome 13/Joubert Syndrome 29
In 2 unrelated infants, born of consanguineous Saudi parents, with Meckel syndrome-13 (MKS13; 617562), Shaheen et al. (2015) identified a homozygous loss-of-function mutation in the TMEM107 gene (616183.0001). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in both families; haplotype analysis indicated a founder effect. Patient cells showed a significant reduction in the number of ciliated cells compared to control cells, as well as abnormal cilia that were excessively elongated with a curly pattern. Patient fibroblasts also showed suppression of SHH (600725) signaling and reduced translocation of SMO (601500) to the cilium compared to control cells. The findings, similar to those observed in mice with loss of Tmem107 function (see ANIMAL MODEL), suggested that loss of TMEM107 impairs ciliogenesis. The families were from a cohort of 25 MKS families who underwent genetic analysis.
In a 22-year-old man with Joubert syndrome-29 (JBTS29; see 617562), Lambacher et al. (2016) identified compound heterozygous mutations in the TMEM107 gene (616183.0002 and 616183.0004). The mutations segregated with the disorder in the family. Patient fibroblasts showed reduced ciliation, and the cilia that formed were abnormally long.
Orofaciodigital Syndrome XVI
In female twins, born of consanguineous parents, with orofaciodigital syndrome XVI (OFD16; 617563), Lambacher et al. (2016) identified a homozygous missense mutation in the TMEM107 gene (E45G; 616183.0003). The mutation segregated with the disorder in the family and was not found in the Exome Variant Server or ExAC databases. The E45G mutant protein retained the ability to localize to the TZ, indicating that the mutation disrupted TMEM107 functions at the TZ, rather than having a gross effect on TMEM107 localization or stability.
In a patient with OFD16, Shylo et al. (2016) identified a homozygous in-frame deletion in the TMEM107 gene (phe106del; 616183.0002). Patient cells showed fewer cilia, and cilia that were formed had a very broad range of lengths compared to controls. The findings indicated that the mutation disrupted cilia formation or maintenance. Patient cilia also showed loss of certain TZ proteins.
Using a forward genetic screen, Christopher et al. (2012) created the 'schlei' mutant mouse, which exhibited preaxial polydactyly, exencephaly, and disrupted ventral neural tube patterning. The defects were consistent with defective ciliary signaling via Shh (600725). Schlei mutants had reduced numbers of cilia in limb mesenchyme and in the lumen of the neural tube. They also had bulged or curled cilia, abnormally thin cilia in the neural tube, and changes in the positions of neural progenitors, consistent with altered fields of Shh responsiveness. Schlei mutant embryos showed normal nodal cilia and normal left-right patterning, and they lacked kidney or liver cysts. Christopher et al. (2012) identified the schlei mutation as an A-to-G transition in the Tmem107 gene, resulting in the substitution of a highly conserved glutamic acid with glycine (E125G) in transmembrane domain-4. Analysis of embryos doubly mutant for schlei and various components of the Shh pathway showed that Tmem107 functioned downstream of Shh, Ptch1 (601309), and Smo (SMOH; 601500) and acted synergistically with Gli2 (165230) and Gli3 (165240) to pattern ventral and intermediate neuronal cell types. Expanded expression of the Shh targets Gli1 (GLI; 165220) and gremlin (603054) in schlei mutant limbs suggested a broadened response to Shh signaling, and the schlei mutation reduced Gli3 function to regulate digit number, but not identity.
In 2 unrelated infants, born of consanguineous Saudi parents, with Meckel syndrome-13 (MKS13; 617562), Shaheen et al. (2015) identified a homozygous G-to-A transition in intron 3 of the TMEM107 gene (c.274+1G-A, NM_032354.3), resulting in a splice site alteration, a frameshift, and premature termination (Ser92CysfsTer7). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in both families. It was not found in the ExAC database or in 573 control Saudi exomes. Haplotype analysis indicated a founder effect. Studies of patient cells showed an overall reduction of mRNA, likely due to nonsense-mediated decay, as well as an altered transcript, consistent with a loss of function. Patient cells showed a significant reduction in the number of ciliated cells compared to controls, as well as abnormal cilia that were excessively elongated with a curly pattern. Patient fibroblasts also showed suppression of SHH (600725) signaling and reduced translocation of SMO (601500) to the cilium compared to control cells. The findings, similar to those observed in mice with loss of Tmem107 function, suggested that loss of TMEM107 impairs ciliogenesis.
In a patient with orofaciodigital syndrome XVI (OFD16; 617563), Shylo et al. (2016) identified a homozygous 3-bp deletion (c.316delTTC, NM_032354.3) in the TMEM107 gene, resulting in an in-frame deletion of a conserved residue (phe106del, F106del) in the third transmembrane domain. Patient cells showed fewer cilia, and cilia that were formed had a very broad range of lengths compared to controls. The findings indicated that the mutation disrupted cilia formation or maintenance. Patient cilia also showed loss of certain transition zone (TZ) proteins.
In a 22-year-old man with Joubert syndrome-29 (JBTS29; see 617562), Lambacher et al. (2016) identified compound heterozygous mutations in the TMEM107 gene: F106del (g.8077890_8077893delGAA) and a 1-bp deletion resulting in a frameshift and premature termination (Leu134PhefsTer8; 616183.0004). The mutations segregated with the disorder in the family and were not found in the Exome Variant Server or ExAC databases. Patient fibroblasts showed reduced ciliation, and the cilia that formed were abnormally long. The F106del mutant protein retained the ability to localize to the TZ, indicating that the mutation disrupted TMEM107 functions at the TZ, rather than having a gross effect on TMEM107 localization or stability.
In female twins, born of consanguineous parents, with orofaciodigital syndrome XVI (OFD16; 617563), Lambacher et al. (2016) identified a homozygous mutation in the TMEM107 gene (g.8079298T-C), resulting in a glu45-to-gly (E45G) substitution. The mutation segregated with the disorder in the family and was not found in the Exome Variant Server or ExAC databases. The E45G mutant protein retained the ability to localize to the TZ, indicating that the mutation disrupted TMEM107 functions at the TZ, rather than having a gross effect on TMEM107 localization or stability.
In a 22-year-old man with Joubert syndrome-29 (JBTS29; see 617562), Lambacher et al. (2016) identified compound heterozygous mutations in the TMEM107 gene: a 1-bp deletion (g.8077560delT) resulting in a frameshift and premature termination (Leu134PhefsTer8) and an in-frame deletion (phe106del; 616183.0002). The mutations segregated with the disorder in the family and were not found in the Exome Variant Server or ExAC databases. Patient fibroblasts showed reduced ciliation, and the cilia that formed were abnormally long.
Christopher, K. J., Wang, B., Kong, Y., Weatherbee, S. D. Forward genetics uncovers transmembrane protein 107 as a novel factor required for ciliogenesis and Sonic hedgehog signaling. Dev. Biol. 368: 382-392, 2012. [PubMed: 22698544] [Full Text: https://doi.org/10.1016/j.ydbio.2012.06.008]
Hartz, P. A. Personal Communication. Baltimore, Md. 1/12/2015.
Lambacher, N. J., Bruel, A.-L., van Dam, T. J. P., Szymanska, K., Slaats, G. G., Kuhns, S., McManus, G. J., Kennedy, J. E., Gaff, K., Wu, K. M., van der Lee, R., Burglen, L., and 12 others. TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubert syndrome. Nature Cell Biol. 18: 122-131, 2016. [PubMed: 26595381] [Full Text: https://doi.org/10.1038/ncb3273]
Shaheen, R., Almoisheer, A., Faqeih, E., Babay, Z., Monies, D., Tassan, N., Abouelhoda, M., Kurdi, W., Al Mardawi, E., Khalil, M. M. I., Seidahmed, M. Z., Alnemer, M., and 9 others. Identification of a novel MKS locus defined by TMEM107 mutation. Hum. Molec. Genet. 24: 5211-5218, 2015. [PubMed: 26123494] [Full Text: https://doi.org/10.1093/hmg/ddv242]
Shylo, N. A., Christopher, K. J., Iglesias, A., Daluiski, A., Weatherbee, S. D. TMEM107 is a critical regulator of ciliary protein composition and is mutated in orofaciodigital syndrome. Hum. Mutat. 37: 155-159, 2016. [PubMed: 26518474] [Full Text: https://doi.org/10.1002/humu.22925]