Alternative titles; symbols
HGNC Approved Gene Symbol: RETREG1
SNOMEDCT: 860810005;
Cytogenetic location: 5p15.1 Genomic coordinates (GRCh38) : 5:16,473,053-16,616,997 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5p15.1 | Neuropathy, hereditary sensory and autonomic, type IIB | 613115 | Autosomal recessive | 3 |
By searching a region of chromosome 5p amplified in esophageal squamous cell carcinoma (ESCC; see 133239) in a Chinese population, Tang et al. (2007) identified FAM134B, which they called JK1. The deduced 39.3-kD protein has an EGF (131530)-like domain, 3 N-glycosylation sites, 3 N-myristoylation sites, and numerous possible phosphorylation sites.
Kurth et al. (2009) stated that the human FAM134B protein contains 497 amino acids. Structure analysis showed that the N-terminal half of FAM134B has 2 unusually long hydrophobic segments of about 35 amino acids each that are separated by a hydrophilic loop of about 60 amino acids. This structure is similar to that of reticulon proteins (see 600865) that shape the curvature of endoplasmic reticulum membranes. The C terminus of FAM134B contains a coiled-coil domain. Northern blot analysis of adult mouse tissues detected at least 4 Fam134b transcripts. High expression of an approximately 1.5-kb transcript was detected in testis only. Transcripts of about 3.5 kb were more weakly expressed in dorsal root ganglia, esophagus, skeletal muscle, and kidney, and many other tissues showed much weaker Fam134b expression. In situ hybridization of day-14.5 mouse embryos showed prominent staining of sensory and autonomic ganglia. In cultured mouse dorsal root ganglia, Fam134b colocalized with a cis-Golgi marker and partly colocalized with a trans-Golgi marker.
Using multiplex RT-PCR, Tang et al. (2007) found that JK1 was overexpressed in a significant number of ESCC cell lines and tumors compared with normal esophageal cells and tissues. Overexpression of JK1 in NIH-3T3 mouse fibroblasts and HEK293 cells caused an increase in growth rate, colony formation in soft agar, and foci formation in confluent cultures. High-grade sarcomas were formed in athymic nude mice following subcutaneous injection of JK1-overexpressing NIH-3T3 cells.
Khaminets et al. (2015) showed that members of the FAM134 reticulon protein family are endoplasmic reticulum (ER)-resident receptors that bind to autophagy modifiers LC3 (601242) and GABARAP (605125), and facilitate ER degradation by autophagy ('ER-phagy'). Downregulation of FAM134B protein in human cells causes an expansion of the ER, while FAM134B overexpression results in ER fragmentation and lysosomal degradation. Mutant FAM134B proteins that cause sensory neuropathy in humans (HSAN2B; 613115) are unable to act as ER-phagy receptors. Consistently, disruption of Fam134b in mice causes expansion of the ER, inhibits ER turnover, sensitizes cells to stress-induced apoptotic cell death, and leads to degeneration of sensory neurons. Therefore, Khaminets et al. (2015) concluded that selective ER-phagy via FAM134 proteins is indispensable for mammalian cell homeostasis and controls ER morphology and turnover in mice and humans.
By genomic sequence analysis, Tang et al. (2007) mapped the FAM134B gene to chromosome 5p15.1, downstream of the delta-catenin gene (CTNND2; 604275).
In affected members of 4 unrelated families with hereditary sensory and autonomic neuropathy type IIB (HSAN2B; 613115), Kurth et al. (2009) identified 4 different homozygous truncating loss-of-function mutations in the FAM134B gene (613114.0001-613114.0004).
In 2 sibs, born of consanguineous Turkish parents, with HSAN2B, Ilgaz Aydinlar et al. (2014) identified a homozygous truncating mutation in the FAM134B gene (613114.0005). Functional studies of the variant and studies on patient cells were not performed.
In 4 affected members of a consanguineous Saudi Arabian family with hereditary sensory and autonomic neuropathy type IIB (HSAN2B; 613115), Kurth et al. (2009) identified a homozygous 926C-G transversion in the FAM134B gene, resulting in a ser309-to-ter (S309X) substitution.
In a patient with hereditary sensory and autonomic neuropathy type IIB (HSAN2B; 613115), Kurth et al. (2009) identified a homozygous 2-bp deletion in exon 1 of the FAM134B gene resulting in frameshift and premature termination at residue 133 (Pro7GlyfsTer133).
In 2 sibs with hereditary sensory and autonomic neuropathy type IIB (HSAN2B; 613115), Kurth et al. (2009) identified a homozygous mutation in the FAM134B gene resulting in a gln145-to-ter (Q145X) substitution.
In 2 sibs, born of consanguineous parents, with hereditary sensory and autonomic neuropathy type IIB (HSAN2B; 613115), Kurth et al. (2009) identified a homozygous T-to-C transition in intron 7 of the FAM134B gene (873+2T-C). The mutation results in a stop codon after 4 additional amino acids.
In 2 sibs, born of consanguineous Turkish parents, with hereditary sensory and autonomic neuropathy type IIB (HSAN2B; 613115), Ilgaz Aydinlar et al. (2014) identified a homozygous 1-bp deletion (c.826delA) in the FAM134B gene, predicted to result in a frameshift and premature termination (Ser176ValfsTer8). The mutation was not found in the dbSNP or 1000 Genomes Project databases. Functional studies of the variant and studies on patient cells were not performed.
Ilgaz Aydinlar, E., Rolfs, A., Serteser, M., Parman, Y. Mutation in FAM134B causing hereditary sensory neuropathy with spasticity in a Turkish family. (Letter) Muscle Nerve 49: 774-775, 2014. [PubMed: 24327336] [Full Text: https://doi.org/10.1002/mus.24145]
Khaminets, A., Heinrich, T., Mari, M., Grumati, P., Huebner, A. K., Akutsu, M., Liebmann, L., Stolz, A., Nietzsche, S., Koch, N., Mauthe, M., Katona, I., Qualmann, B., Weis, J., Reggiori, F., Kurth, I., Hubner, C. A., Dikic, I. Regulation of endoplasmic reticulum turnover by selective autophagy. Nature 522: 354-358, 2015. [PubMed: 26040720] [Full Text: https://doi.org/10.1038/nature14498]
Kurth, I., Pamminger, T., Hennings, J. C., Soehendra, D., Huebner, A. K., Rotthier, A., Baets, J., Senderek, J., Topaloglu, H., Farrell, S. A., Nurnberg, G., Nurnberg, P., De Jonghe, P., Gal, A., Kaether, C., Timmerman, V., Hubner, C. A. Mutations in FAM134B, encoding a newly identified Golgi protein, cause severe sensory and autonomic neuropathy. Nature Genet. 41: 1179-1181, 2009. [PubMed: 19838196] [Full Text: https://doi.org/10.1038/ng.464]
Tang, W. K., Chui, C. H., Fatima, S., Kok, S. H. L., Pak, K. C., Ou, T. M., Hui, K. S., Wong, M. M., Wong, J., Law, S., Tsao, S. W., Lam, K. Y., Beh, P. S. L., Srivastava, G., Chan, A. S. C., Ho, K. P., Tang, J. C. O. Oncogenic properties of a novel gene JK-1 located in chromosome 5p and its overexpression in human esophageal squamous cell carcinoma. Int. J. Molec. Med. 19: 915-923, 2007. [PubMed: 17487424]