Alternative titles; symbols
HGNC Approved Gene Symbol: SAR1B
SNOMEDCT: 702364003; ICD10CM: E78.3;
Cytogenetic location: 5q31.1 Genomic coordinates (GRCh38) : 5:134,601,149-134,632,828 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q31.1 | Chylomicron retention disease | 246700 | Autosomal recessive | 3 |
By searching databases, followed by PCR, He et al. (2002) cloned human SAR1B, which they called SARA1. The deduced 198-amino acid SARA1 protein contains 4 highly conserved GTPase motifs. Northern blot analysis detected strong expression of a major transcript of 2.4 to 4.4 kb in all tissues examined. Smaller and larger variants were also detected in most tissues.
By a genomewide screen of 6 affected families to find a gene mutant in lipid absorption disorders, Jones et al. (2003) identified the SAR1B gene, which they called SARA2, in a region of apparent homozygosity on 5q31.1 shared by 4 affected families. SAR1B belongs to the Sar1-ADP-ribosylation factor family of small GTPases (Takai et al., 2001), which govern the intracellular trafficking of proteins in coat protein (COP)-coated vesicles (Schekman and Orci, 1996). The human SARA1B protein shares 99% amino acid identity with hamster Sar1. SARA1B is expressed in many tissues including small intestine, liver, muscle, and brain.
He et al. (2002) determined that the SAR1B gene contains 8 exons and spans over 60 kb.
Jones et al. (2003) determined that the human SAR1B gene comprises 7 exons.
By radiation hybrid analysis, He et al. (2002) mapped the SAR1B gene to chromosome 5q23-q31.1.
The SAR1B gene maps to chromosome 5q31.1, within 94 kb of the SEC24A gene (607183) (Jones et al., 2003).
Chylomicron retention disease (CMRD; 246700), also known as Anderson disease, is an autosomal recessive disorder of severe fat malabsorption associated with failure to thrive in infancy. The condition is characterized by deficiency of fat-soluble vitamins, low blood cholesterol levels, and a selective absence of chylomicrons from blood. Affected individuals accumulate chylomicron-like particles in membrane-bound compartments of enterocytes, which contain large cytosolic lipid droplets. In affected members of several families with CMRD, Jones et al. (2003) identified homozygous or compound heterozygous mutations in the SAR1B gene (607690.0001-607690.0006). Jones et al. (2003) found no mutations in a second human isoform SAR1A (607691), located on chromosome 10, in families with these disorders.
Charcosset et al. (2008) identified mutations in the SAR1B gene (see, e.g., 607690.0007; 607690.0008) in families with CMRD.
In 2 members of an Algerian family with chylomicron retention disease (CMRD; 246700), Jones et al. (2003) identified homozygosity for a 109G-A transition in the SAR1B gene that caused a gly37-to-arg (G37R) amino acid change, with the result that the protein had no affinity for GDP/GTP. Both parents were heterozygous.
In 2 white Canadian families, Jones et al. (2003) found that affected individuals with chylomicron retention disease (CMRD; 246700) were homozygous for a 409G-A transition in the SAR1B gene that resulted in an asp137 amino acid change (D137N) and reduced affinity of the protein for GDP/GTP. In a third white Canadian family, a single affected individual was a compound heterozygote for the D137N mutation and a deletion of 2 nucleotides, 75_76delTG (607690.0003). The change occurring in leu28 resulted in frameshift and premature termination at codon 34 (Leu28fsTer34).
Charcosset et al. (2008) identified the D137N mutation in 3 additional French Canadian families with chylomicron retention disease.
For discussion of the 2-bp deletion (75_76delTG) in the SAR1B gene, resulting in a frameshift and premature termination at codon 34 (Leu28fsTer34), that was found in compound heterozygous state in a white Canadian individual with chylomicron retention disease (CMRD; 246700) by Jones et al. (2003), see 607690.0002.
In a white Canadian family, Jones et al. (2003) found that chylomicron retention disease (CMRD; 246700) was associated with homozygosity for a ser179-to-arg (S179R) mutation arising from a 537T-A transversion in the SAR1B gene that resulted in loss of affinity of the protein for GDP/GTP.
Charcosset et al. (2008) identified the S179R mutation in 3 additional French Canadian families with chylomicron retention disease.
In a Turkish family, Jones et al. (2003) demonstrated that 2 children with chylomicron retention disease (CMRD; 246700) were homozygous for a 4-bp duplication of 555_556dupTTAC in the SAR1B gene. The mutated allele replaced amino acids 187-198 of the SARA2 protein with a new amino acid sequence. The translation was arrested after codon 198. The mutation was predicted to affect helix 6 and to cause reduced affinity for the endoplasmic reticulum (ER) membrane.
In an Italian family in which 2 brothers had chylomicron retention disease (CMRD; 246700) and Marinesco-Sjogren syndrome (MSS; 248800), reported by Aguglia et al. (2000), Jones et al. (2003) found homozygosity for a splice site mutation in the SAR1B gene (349-1G-C). It was predicted that this mutation could cause exon skipping, activation of a nearby cryptic splice site, or production of an unspliced mRNA, any of which would substantially disrupt the protein. In the same patients, Annesi et al. (2007) identified a mutation in the SIL1 gene (R111X; 608005.0004), responsible for MSS. The findings indicated that the patients had 2 distinct diseases due to mutations in 2 different genes, rather than defects in a single gene leading to both disorders.
In affected members of a Turkish family with chylomicron retention disease (CMRD; 246700), Charcosset et al. (2008) identified a homozygous 364G-C transversion in the SAR1B gene, resulting in a glu122-to-ter (E122X) substitution.
In a Portuguese child with chylomicron retention disease (CMRD; 246700), Charcosset et al. (2008) identified a homozygous 554G-T transversion in the SAR1B gene, resulting in a gly185-to-val (G185V) substitution.
Aguglia, U., Annesi, G., Pasquinelli, G., Spadafora, P., Gambardella, A., Annesi, F., Pasqua, A. A., Cavalcanti, F., Crescibene, L., Bagala, A., Bono, F., Oliveri, R. L., Valentino, P., Zappia, M., Quattrone, A. Vitamin E deficiency due to chylomicron retention disease in Marinesco-Sjogren syndrome. Ann. Neurol. 47: 260-264, 2000. [PubMed: 10665502]
Annesi, G., Aguglia, U., Tarantino, P., Annesi, F., De Marco, E. V., Civitelli, D., Torroni, A., Quattrone, A. SIL1 and SARA2 mutations in Marinesco-Sjogren and chylomicron retention disease. (Letter) Clin. Genet. 71: 288-289, 2007. [PubMed: 17309654] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00759.x]
Charcosset, M., Sassolas, A., Peretti, N., Roy, C. C., Deslandres, C., Sinnett, D., Levy, E., Lachaux, A. Anderson or chylomicron retention disease: molecular impact of five mutations in the SAR1B gene on the structure and the functionality of Sar1b protein. Molec. Genet. Metab. 93: 74-84, 2008. [PubMed: 17945526] [Full Text: https://doi.org/10.1016/j.ymgme.2007.08.120]
He, H., Dai, F., Yu, L., She, X., Zhao, Y., Jiang, J., Chen, X., Zhao, S. Identification and characterization of nine novel human small GTPases showing variable expressions in liver cancer tissues. Gene Expr. 10: 231-242, 2002. [PubMed: 12450215] [Full Text: https://doi.org/10.3727/000000002783992406]
Jones, B., Jones, E. L., Bonney, S. A., Patel, H. N., Mensenkamp, A. R., Eichenbaum-Voline, S., Rudling, M., Myrdal, U., Annesi, G., Naik, S., Meadows, N., Quattrone, A., and 9 others. Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders. Nature Genet. 34: 29-31, 2003. [PubMed: 12692552] [Full Text: https://doi.org/10.1038/ng1145]
Schekman, R., Orci, L. Coat proteins and vesicle budding. Science 271: 1526-1533, 1996. [PubMed: 8599108] [Full Text: https://doi.org/10.1126/science.271.5255.1526]
Takai, Y., Sasaki, T., Matozaki, T. Small GTP-binding proteins. Physiol. Rev. 81: 154-208, 2001. [PubMed: 11152757] [Full Text: https://doi.org/10.1152/physrev.2001.81.1.153]