Alternative titles; symbols
HGNC Approved Gene Symbol: FAM149B1
Cytogenetic location: 10q22.2 Genomic coordinates (GRCh38): 10:73,168,119-73,244,504 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q22.2 | Joubert syndrome 36 | 618763 | Autosomal recessive | 3 |
The FAM149B1 gene encodes a protein that is expressed in early mouse embryonic stages and is thought to play a role in primary cilia biology (summary by Shaheen et al., 2019).
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1999) cloned FAM149B1, which they designated KIAA0974. The deduced protein contains 565 amino acids. RT-PCR ELISA showed ubiquitous FAM149B1 expression in human tissues, with highest expression in kidney, testis, and ovary.
Gross (2019) mapped the FAM149B1 gene to chromosome 10q22.2 based on an alignment of the FAM149B1 sequence (GenBank BC015394) with the genomic sequence (GRCh38).
In 6 patients from 4 unrelated consanguineous families of Middle Eastern descent with Joubert syndrome-36 (JBTS36; 618763), Shaheen et al. (2019) identified homozygosity for a frameshift or a nonsense mutation in the FAM149B1 gene (618413.0001-618413.0002). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. One variant was not found in the gnomAD database, whereas the other was found at a low frequency. Fibroblasts derived from 1 patient showed longer cilia and greater variability of cilia length compared to controls. Immunostaining showed abnormal accumulation of IFT88 (600595) and IFT46 (620506) at the tip of the cilia resulting in a bulging morphology, suggesting impaired retrograde transport. Patient cells and HEK293 cells with siRNA-mediated knockdown of FAM149B1 showed significant dysregulation of SHH (600725) compared to controls. In addition, Shaheen et al. (2019) confirmed that FAM149B1 interacts with TBC1D32 (615867), which has been associated with an OFD phenotype in 1 patient (see 615867.0001). Cells derived from that patient also showed abnormal accumulation of IFT complex at the tip of the cilia and showed a similar gene expression profile as fibroblasts from the patient with the FAM149B1 mutation. Shaheen et al. (2019) concluded that FAM149B1 is required for normal ciliary development.
In 5 patients from 3 consanguineous Arab families (families 1-3) with Joubert syndrome-36 (JBTS36; 618763), Shaheen et al. (2019) identified a homozygous 2-bp deletion (c.356_357delAG, NM_173348.1) in exon 4 of the FAM149B1 gene, resulting in a frameshift and premature termination (Lys119IlefsTer18). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. It was not present in the gnomAD database or in a database of 2,379 ethnically matched control exomes. Haplotype analysis confirmed a founder effect. Fibroblasts derived from 1 patient showed longer cilia and greater variability of cilia length compared to controls. Immunostaining showed abnormal accumulation of IFT88 (600595) and IFT46 at the tip of the cilia resulting in a bulging morphology, suggesting impaired retrograde transport. Patient cells and HEK293 cells with siRNA-mediated knockdown of FAM149B1 showed significant dysregulation of SHH (600725) compared to controls.
In a boy, born of consanguineous Turkish parents (family 4), with Joubert syndrome-36 (JBTS36; 618763), Shaheen et al. (2019) identified a homozygous c.439C-T transition (c.439C-T, NM_173348.1) in the FAM149B1 gene, resulting in a gln1147-to-ter (Q1147X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was found at a low frequency (6.637 x 10(-6)) in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
Gross, M. B. Personal Communication. Baltimore, Md. 5/3/2019.
Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 63-70, 1999. [PubMed: 10231032] [Full Text: https://doi.org/10.1093/dnares/6.1.63]
Shaheen, R., Jiang, N., Alzahrani, F., Ewida, N., Al-Sheddi, T., Alobeid, E., Musaev, D., Stanley, V., Hashem, M., Ibrahim, N., Abdulwahab, F., Alshenqiti, A., Sonmez, F. M., Saqati, N., Alzaidan, H., Al-Qattan, M. M., Al-Mohanna, F., Gleeson, J. G., Alkuraya, F. S. Bi-allelic mutations in FAM149B1 cause abnormal primary cilium and a range of ciliopathy phenotypes in humans. Am. J. Hum. Genet. 104: 731-737, 2019. [PubMed: 30905400] [Full Text: https://doi.org/10.1016/j.ajhg.2019.02.018]