Alternative titles; symbols
HGNC Approved Gene Symbol: BAAT
Cytogenetic location: 9q31.1 Genomic coordinates (GRCh38): 9:101,360,417-101,385,006 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q31.1 | Bile acid conjugation defect 1 | 619232 | Autosomal recessive | 3 |
The BAAT gene encodes an enzyme that catalyzes the addition of glycine or taurine to C24 bile acids in the hepatocyte. This conjugation enhances aqueous solubility at the pH of the proximal intestine where the conjugated bile acids are secreted. This increases intraluminal bile acid concentrations for solubilization and subsequent absorption of lipids, saturated fatty acids, and fat-soluble vitamins (summary by Setchell et al., 2013).
The major solutes in bile are N-acyl conjugates of cholanoates (C24 bile acids) with glycine or taurine. These bile acid-amino acid conjugates serve as detergents in the gastrointestinal tract. Bile acid-amino acid conjugates are formed in the liver via a 2-step pathway. The first reaction converts a bile acid to an acyl-CoA thioester and is catalyzed by the microsomal enzyme, cholyl-CoA synthetase (EC 6.2.1.7). The second reaction transfers the bile acid moiety from the acyl-CoA thioester to either glycine or taurine, and is catalyzed by bile acid-CoA:amino acid N-acyltransferase (BAAT; EC 2.3.1.65).
Johnson et al. (1991) purified human liver BAAT, and demonstrated that it is a 50-kD monomeric enzyme. By screening a liver expression library with antibodies against human BAAT, Falany et al. (1994) isolated cDNAs encoding BAAT. The predicted protein contain 418 amino acids.
Lench et al. (1996) created an EST- and STS-based YAC contig map of 9q22.3 and showed that it contains the following genes in this order (from centromere to telomere): TMOD (190930), XPA (611153), ALDOB (612724), BAAT. All 4 of these genes map to a syntenic region of mouse chromosome 4 and are situated in the same order as their counterparts on human 9q22.3.
In 4 children from 2 unrelated families (families 9 and 10) of Old Order Amish descent with bile acid conjugation defect-1 (BACD1; 619232), Carlton et al. (2003) identified a homozygous missense variant in the BAAT gene (M76V; 602938.0001). The mutation, which was found by a combination of linkage analysis and candidate gene sequencing, was demonstrated to segregate with the phenotype in 1 family. The BAAT mutation was not seen in 182 control chromosomes from Caucasian subjects and was seen in only 1 of 104 control chromosomes from Lancaster County Old Order Amish individuals. Another Amish patient (patient 11) who was homozygous for the M76V mutation also carried a heterozygous variant in the TJP2 gene (V48A; 607709.0001). Carlton et al. (2003) postulated that in individuals homozygous for the BAAT M76V mutation, unconjugated bile acids do not translocate into bile, such that most bile acids diffuse back into the plasma from the hepatocytes. This leads to high serum concentrations and low intestinal concentrations of unconjugated bile acids. Several additional Amish individuals with a similar phenotype were heterozygous for the BAAT M76V mutation and homozygous for the TJP2 V48A variant, suggesting oligogenic inheritance.
In 7 patients from 4 unrelated families with BACD1, Setchell et al. (2013) identified 4 different homozygous mutations in the BAAT gene (602938.0002-602938.0005), including 3 missense and 1 nonsense. The mutations, which were found by direct sequencing of the BAAT gene, segregated with the disorder in the families. Functional studies of the variants and studies of patient cells were not performed, but immunostaining showed absence of BAAT expression in patient liver biopsies, consistent with a loss of function.
In 4 children from 2 unrelated families (families 9 and 10) with bile acid conjugation defect-1 (BACD1; 619232), Carlton et al. (2003) identified a homozygous c.226A-G transition in the BAAT gene, predicted to result in a met76-to-val (M76V) substitution. The mutation, which was found by a combination of linkage analysis and candidate gene sequencing, was demonstrated to segregate with the phenotype in 1 family. The BAAT mutation was not seen in 182 control chromosomes from Caucasian subjects and was seen in only 1 of 104 control chromosomes from Lancaster County Old Order Amish individuals. Several additional Amish individuals with a similar phenotype were heterozygous for the BAAT M76V mutation and homozygous for a missense variant in the TJP2 gene (V48A; 607709), suggesting oligogenic inheritance. One patient (patient 11) was homozygous for the BAAT mutation and heterozygous for the TJP2 mutation.
In 2 sibs (patients 2 and 3 from family 2) with bile acid conjugation defect-1 (BACD1; 619232), Setchell et al. (2013) identified a homozygous c.1156G-A transition in the BAAT gene, resulting in a gly386-to-arg (G386R) substitution. The mutation, which was found by direct sequencing, was predicted to impact protein structure or function, although functional studies were not performed.
In a patient (patient 4 from family 3) with bile acid conjugation defect-1 (BACD1; 619232), Setchell et al. (2013) identified a homozygous c.206A-T transversion in the BAAT gene, resulting in an asp69-to-val (D69V) substitution. The mutation, which was found by direct sequencing, was predicted to impact protein structure or function, although functional studies were not performed.
In 3 sibs (patients 5-7 from family 4) with bile acid conjugation defect-1 (BACD1; 619232), Setchell et al. (2013) identified a homozygous c.58C-T transition in the BAAT gene, resulting in an arg20-to-ter (R20X) substitution. The mutation, which was found by direct sequencing, was predicted to impact protein structure or function, although functional studies were not performed.
In a female infant (patient 8 from family 5) with bile acid conjugation defect-1 (BACD1; 619232), Setchell et al. (2013) identified a homozygous c.250C-A transversion in the BAAT gene, resulting in a pro84-to-thr (P84T) substitution. The mutation, which was found by direct sequencing, was predicted to impact protein structure or function, although functional studies were not performed.
Carlton, V. E. H., Harris, B. Z., Puffenberger, E. G., Batta, A. K., Knisely, A. S., Robinson, D. L., Strauss, K. A., Shneider, B. L., Lim, W. A., Salen, G., Morton, D. H., Bull, L. N. Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT. Nature Genet. 34: 91-96, 2003. [PubMed: 12704386] [Full Text: https://doi.org/10.1038/ng1147]
Falany, C. N., Johnson, M. R., Barnes, S., Diasio, R. B. Glycine and taurine conjugation of bile acids by a single enzyme: molecular cloning and expression of a human liver bile acid CoA:amino acid N-acyltransferase. J. Biol. Chem. 269: 19375-19379, 1994. [PubMed: 8034703]
Johnson, M. R., Barnes, S., Kwakye, J. B., Diasio, R. B. Purification and characterization of bile acid-CoA:amino acid N-acyltransferase from human liver. J. Biol. Chem. 266: 10227-10233, 1991. [PubMed: 2037576]
Lench, N. J., Telford, E. A., Andersen, S. E., Moynihan, T. P., Robinson, P. A., Markham, A. F. An EST and STS-based YAC contig map of human chromosome 9q22.3 Genomics 38: 199-205, 1996. [PubMed: 8954802] [Full Text: https://doi.org/10.1006/geno.1996.0616]
Setchell, K. D. R., Heubi, J. E., Shah, S., Lavine, J. E., Suskind, D., Al-Edreesi, M., Potter, C., Russell, D. W., O'Connell, N. C., Wolfe, B., Jha, P., Zhang, W., Bove, K. E., Knisely, A. S., Hofmann, A. F., Rosenthal, P., Bull, L. N. Genetic defects in bile acid conjugation cause fat-soluble vitamin deficiency. Gastroenterology 144: 945-955, 2013. [PubMed: 23415802] [Full Text: https://doi.org/10.1053/j.gastro.2013.02.004]