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Alternative titles; symbolsBUP1BETA-ALANINE SYNTHASEHGNC Approved Gene Symbol: UPB1Cytogenetic location: 22q11.23 Genomic coordinates (GRCh38): 22:24,495,059...

Alternative titles; symbols

  • BUP1

HGNC Approved Gene Symbol: UPB1

Cytogenetic location: 22q11.23 Genomic coordinates (GRCh38): 22:24,495,059-24,528,680 (from NCBI)

▼ Description
The UPB1 gene encodes beta-ureidopropionase (EC, which catalyzes the last step in pyrimidine degradation, converting N-carbamyl-beta-aminoisobutyric acid and N-carbamyl-beta-alanine to, respectively, beta-aminoisobutyric acid (see 210100) and beta-alanine, ammonia, and carbon dioxide (Vreken et al., 1999).

▼ Cloning and Expression
Vreken et al. (1999) cloned the BUP1 gene. The BUP1 open reading frame of 1,152 bp corresponds to a protein of 384 amino acids with a calculated molecular mass of 43 kD, surrounded by a 5-prime untranslated region of 61 nucleotides and a 3-prime untranslated region of 277 nucleotides. The protein shows 84% identity with the translation product of the rat beta-ureidopropionase cDNA. Expression of the human cDNA in Escherichia coli and eukaryotic COS-7 cells revealed a very high beta-ureidopropionase enzymatic activity, thus confirming the identity of the cDNA. Human EST libraries from brain, liver, kidney, and heart contained partial beta-ureidopropionase cDNAs, suggesting expression in these tissues, as seen in the rat.

▼ Gene Structure
Vreken et al. (1999) determined that the BUP1 gene consists of 11 exons and spans approximately 20 kb of genomic DNA.

▼ Mapping
Vreken et al. (1999) mapped the human UPB1 gene to chromosome 22q11.2 by fluorescence in situ hybridization.

▼ Gene Function
Beta-ureidopropionase has also been named beta-alanine synthase, since it catalyzes the biosynthesis of beta-alanine in animals. In its active form, the enzyme exists as a dodecamer or hexamer, whereas the enzyme dissociates into an inactive trimer in response to its product beta-alanine (Matthews et al., 1992).

Sakamoto et al. (2001) found that purified human liver beta-ureidopropionase activity was inhibited by 1 mM propionate, but not by 10 mM beta-alanine. In this regard it differs from rat liver enzyme.

▼ Molecular Genetics
Van Kuilenburg et al. (2004) reported 3 mutant alleles in the UPB1 gene among 4 patients with beta-ureidopropionase deficiency (UPB1D; 613161). These mutations included 2 splice site mutations (IVS1-2A-G, 606673.0001 and IVS8-1G-A, 606673.0002) and 1 missense mutation (A85E; 606673.0003). Heterologous expression of the A85E mutant enzyme in E. coli yielded no residual activity. The authors speculated that an altered homeostasis of beta-aminoisobutyric acid and/or increased oxidative stress might contribute to some of the clinical abnormalities encountered in these patients.

▼ ALLELIC VARIANTS ( 4 Selected Examples):

UPB1, IVS1AS, A-G, -2
In the original patient with beta-ureidopropionase deficiency (UPB1D; 613161) described by Assmann et al. (1998), van Kuilenburg et al. (2004) found compound heterozygosity for 2 splice acceptor site mutations in the UPB1 gene, IVS1-2A-G and IVS8-1G-A (606673.0002).

Van Kuilenburg et al. (2004) described a 3-year-old Turkish girl, born of consanguineous parents, who had psychomotor and severe mental retardation attributed to beta-ureidopropionase deficiency. The child was homozygous for the IVS1-2A-G mutation. The mutation was predicted to result in a frameshift downstream of exon 1.

UPB1, IVS8AS, G-A, -1
In a 4-month-old boy, born of nonconsanguineous parents, who had no detectable beta-ureidopropionase activity in a liver biopsy (UPB1D; 613161), van Kuilenburg et al. (2004) found homozygosity for a splice site mutation, IVS8-1G-A, in the UPB1 gene. The mutation was predicted to result in a frameshift downstream of exon 8.

Van Kuilenburg et al. (2004) found the original beta-ureidopropionase deficiency patient described by Assmann et al. (1998) to be compound heterozygous for this and another splice site mutation, IVS1-2A-G (606673.0001).

In a 12-month-old African girl, born of nonconsanguineous parents, with beta-ureidopropionase deficiency (UPB1D; 613161), van Kuilenburg et al. (2004) detected a 254C-A transversion in exon 2 of the UPB1 gene that resulted in an ala85-to-glu (A85E) substitution. Heterologous expression of the mutant enzyme in E. coli revealed no endogenous beta-ureidopropionase activity.

In an Australian boy with beta-ureidopropionase deficiency (UPB1D; 613161), Yaplito-Lee et al. (2008) identified compound heterozygosity for 2 mutations in the UPB1 gene: a 209G-C transversion in exon 2, resulting in an arg70-to-pro (R70P) substitution, and a splice site mutation (606673.0001). He had multiple congenital genitourinary and colorectal anomalies, including bladder exstrophy, anal atresia, duplicated appendix and distal colon, and bifid phallus and scrotum. Renal imaging showed moderate pelvicalyceal and ureteric dilatation and echogenic areas. At age 12 months, he showed normal growth, development, and neurologic examination. In vitro functional expression studies showed that the R70P mutant protein had no residual activity.

Tags: 22q11.23