Alternative titles; symbols
HGNC Approved Gene Symbol: PCBD1
Cytogenetic location: 10q22.1 Genomic coordinates (GRCh38): 10:70,882,280-70,888,565 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q22.1 | Hyperphenylalaninemia, BH4-deficient, D | 264070 | Autosomal recessive | 3 |
The PCBD1 gene encodes a bifunctional protein that acts as an enzyme in the salvage pathway for regeneration of tetrahydrobiopterin (BH4), the cofactor for aromatic amino acid hydroxylases. It also acts as a binding partner of the HNF1 family of transcription factors (see 142410) (Thony et al., 1998).
Pterin carbinolamine dehydratase/dimerization cofactor of HNF1 (PCBD/DCOH) is a dual-function protein. In the cytoplasm it acts as a dehydratase in the regeneration of BH4, whereas in the nucleus, it functions as a dimerization cofactor of HNF1 and increases the transcriptional activity of HNF1 (Lei and Kaufman, 1999).
Dimerization among transcription factors is a recurrent theme in the regulation of eukaryotic gene expression. HNF1 is a homeodomain-containing protein that functions as a dimer. Mendel et al. (1991) identified a dimerization cofactor of HNF-1-alpha (DCOH) that displayed a restricted tissue distribution.
Hauer et al. (1993) isolated cDNA clones corresponding to the pterin-4-alpha-carbinolamine dehydratase gene from a human liver cDNA library. The human and rat proteins have identical sequences and a molecular mass of 11.9 kD. The PCBD1 protein was identical to the dimerization cofactor reported by Mendel et al. (1991). The protein was found to exist as a tetramer.
Lei and Kaufman (1999) found that human PCBD/DCOH was present predominantly in liver and kidney, with significant amounts in testis and ovary, trace amounts in lung, and undetectable levels in whole brain, heart, and spleen. It was expressed in all of the cells that were examined. It was also present in the nucleus of HeLa cells, which lack HNF1, and in the cytoplasm of fibroblasts, that have little or no BH4. Although the mRNA level in liver was only 4-fold higher than that in keratinocytes and fibroblasts, the hepatic protein level was 20-fold higher than that in keratinocytes and dermal fibroblasts. Further studies showed that the untranslated region of human keratinocyte PCBD had 53 bp more than the liver PCBD, which made a difference in translation efficiency. These data show that PCBD is a widely distributed protein, with differential expression in different tissues and cells that is regulated at both the transcriptional and translational levels.
In mice, Ferre et al. (2014) found expression of the Pcbd1 gene in kidney, liver, and pancreatic cells. Pcbd1 localized mostly to the distal convoluted tubule, but als to the cortical thick ascending loop of Henle and connecting tubule.
Simaite et al. (2014) found expression of the Pcbd1 gene in the developing pancreas of both mice and Xenopus. Pcbd1 accumulated in endocrine progenitor cells and endoderm in Xenopus, and in endocrine progenitor cells and pancreatic epithelium in mice.
Using a previously isolated cDNA as a probe, Thony et al. (1995) isolated and determined the complete nucleotide sequence and flanking regions of the single human PCBD gene. The protein coding region of the gene is about 5 kb long and contains 4 exons. The 5-prime flanking sequence was studied, and binding sites for several transcriptional regulators were found.
Mendel et al. (1991) found that DCOH did not bind to DNA but, rather, to selectively stabilized HNF1A dimers.
In mice, Ferre et al. (2014) found expression of Pcbd1 mostly in the distal convoluted tubule of the kidney. Pcbd1 expression increased when mice were fed a low magnesium diet, suggesting that Pcbd1 is important for renal magnesium reabsorption. In vitro studies showed that PCBD1 regulated HNF1B (189907)-mediated transcription of FXYD2 (601814), influencing active renal magnesium absorption.
Milatovich et al. (1993) mapped the DCOH gene to chromosome 10 by Southern blot analysis of somatic cell hybrids. The mouse homolog was mapped to chromosome 10 by study of mouse/Chinese hamster and mouse/rat somatic cell hybrids. Although no polymorphism of the Dcoh gene was found in 5 inbred strains using 18 different restriction enzymes, the fact that the homologous genes on chromosome 10 in the human and the mouse are confined to a single small region suggests that the human DCOH gene is in the region 10q21-q22. By in situ hybridization, Thony et al. (1994) localized the PCBD/DCOH gene to 10q22.
In 6 patients with BH4-deficient hyperphenylalaninemia with high levels of 7-biopterin (HPABH4D; 264070), Thony et al. (1998) demonstrated homozygosity for single-nucleotide mutations in exon 4 of the PCBD gene (126090.0003-126090.0005).
Ferre et al. (2014) found that 5 PCBD1 mutations previously reported in HPABH4D patients (see, e.g., Q87X, 126090.0001; E27X, 126090.0006; Q98X, 126090.0005) resulted in proteolytic instability, leading to reduced FXYD2 promoter activity and increased renal magnesium loss. Cytosolic localization of PCBD1 increased when coexpressed with HNF1B mutants. The findings established PCBD1 as a coactivator of the HNF1B-mediated transcription necessary for fine tuning FXYD2 transcription in the renal distal collecting tubule.
Bayle et al. (2002) found that Dcoh-null mice were viable and fertile and thrived for more than 1 year, but they displayed hyperphenylalaninemia and a predisposition to cataract formation. Hnf1 function was only slightly impaired in Dcoh-null mice, suggesting that Dcoh activity was partially complemented by Dcoh2.
Simaite et al. (2014) found that morpholino knockdown of pcbd1 in Xenopus resulted in a significant reduction in the expression of pancreatic progenitor genes, as well as reduced expression of hnf1b. The finding suggested that pcbd1 activity in Xenopus endoderm is required for proper establishment of the pancreas.
In a 1-year-old Caucasian male with BH4-deficient hyperphenylalaninemia-D (HPABH4D; 264070), Citron et al. (1993) found compound heterozygosity for 2 mutations in the PCBD1 gene: a c.259G-T transversion, resulting in a glu87-to-ter (E87X) substitution, and a c.244T-C transition, resulting in a cys82-to-arg (C82R; 126090.0002) substitution. The nonsense mutation came from the father and the missense mutation from the mother. The patient was found to have mildly increased phenylalanine at newborn screening.
Johnen et al. (1995) characterized the wildtype form of pterin-4-alpha-carbinolamine dehydratase and the 2 naturally occurring mutants C82R and Q87X. Considering the decrease in specific activity and stability of the mutants, they concluded that the patient probably had less than 10% residual dehydratase activity, which could be responsible for the mild hyperphenylalaninemia and the high 7-biopterin levels.
In 2 sibs of Ashkenazi Jewish descent with hyperphenylalaninemia associated with high levels of 7-biopterin (BIODEF273; BIODEF344), Thony et al. (1998) identified a homozygous c.279G-T transversion in the PCBD1 gene, resulting in a glu86-to-ter (E86X) substitution. The first methionine was not included in the numbering used by Thony et al. (1998). Both sibs developed normally without pharmacologic or dietary treatment.
For discussion of the cys82-to-arg (C82R) mutation in the PCBD1 gene that was found in compound heterozygous state in a patient with HPABH4D (264070) by Citron et al. (1993), see 126090.0001.
In a Hispanic brother and sister with hyperphenylalaninemia in combination with urinary primapterin (264070), Thony et al. (1998) identified homozygosity for a C-to-T transition at nucleotide 256 of the bifunctional gene PCBD/DCOH, resulting in a thr78-to-ile (T78I) amino acid substitution. Development was normal in the sibs, on an ordinary diet, at ages 8.5 and 10 years, respectively. The parents were not related. The first methionine was not included in the numbering used by Thony et al. (1998).
In 2 unrelated patients (BIODEF272 and BIODEF264) with hyperphenylalaninemia associated with high levels of 7-biopterin (HPABH4D; 264070), Thony et al. (1998) identified a homozygous c.312C-T transition in the PCBD1 gene, resulting in a gln97-to-ter (Q97X) substitution. Growth and development were normal in both patients. The first methionine was not included in the numbering used by Thony et al. (1998).
Simaite et al. (2014) referred to this mutation as a c.292C-T transition, resulting in a gln98-to-ter (Q98X) substitution.
In a patient (BIODEF329), born of consanguineous Turkish parents, with HPABH4D (264070), Thony et al. (1998) identified homozygosity for 2 mutations in the PCBD1 gene: a c.99G-T transversion, resulting in a glu26-to-ter (E26X) substitution, and a c.283G-A transition, resulting in an arg87-to-gln (R87Q) substitution. Each unaffected parent was heterozygous for the mutant allele, which carried the 2 mutations in cis. The numbering system used by Thony et al. (1998) did not include the first methionine.
Simaite et al. (2014) referred to this mutation as a c.79G-T transversion, resulting in a glu27-to-ter (E27X) substitution, and a c.263G-A transition, resulting in an arg88-to-gln (R88Q) substitution.
Bayle, J. H., Randazzo, F., Johnen, G., Kaufman, S., Nagy, A., Rossant, J., Crabtree, G. R. Hyperphenylalaninemia and impaired glucose tolerance in mice lacking the bifunctional DCoH gene. J. Biol. Chem. 277: 28884-28891, 2002. [PubMed: 12011081] [Full Text: https://doi.org/10.1074/jbc.M201983200]
Citron, B. A., Kaufman, S., Milstien, S., Naylor, E. W., Greene, C. L., Davis, M. D. Mutation in the 4a-carbinolamine dehydratase gene leads to mild hyperphenylalaninemia with defective cofactor metabolism. Am. J. Hum. Genet. 53: 768-774, 1993. [PubMed: 8352282]
Ferre, S., de Baaij, J. H. F., Ferreira, P., Germann, R., de Klerk, J. B. C., Lavrijsen, M., van Zeeland, F., Venselaar, H., Kluijtmans, L. A. J., Hoenderop, J. G. J., Bindels, R. J. M. Mutations in PCBD1 cause hypomagnesemia and renal magnesium wasting. J. Am. Soc. Nephrol. 25: 574-586, 2014. [PubMed: 24204001] [Full Text: https://doi.org/10.1681/ASN.2013040337]
Hauer, C. R., Rebrin, I., Thony, B., Neuheiser, F., Curtius, H.-C., Hunziker, P., Blau, N., Ghisla, S., Heizmann, C. W. Phenylalanine hydroxylase-stimulating protein/pterin-4-alpha-carbinolamine dehydratase from rat and human liver: purification, characterization, and complete amino acid sequence. J. Biol. Chem. 268: 4828-4831, 1993. [PubMed: 8444860]
Johnen, G., Kowlessur, D., Citron, B. A., Kaufman, S. Characterization of the wild-type form of 4a-carbinolamine dehydratase and two naturally occurring mutants associated with hyperphenylalaninemia. Proc. Nat. Acad. Sci. 92: 12384-12388, 1995. Note: Erratum: Proc. Nat. Acad. Sci. 93: 4519 only, 1996. [PubMed: 8618906] [Full Text: https://doi.org/10.1073/pnas.92.26.12384]
Lei, X.-D., Kaufman, S. Characterization of expression of the gene for human pterin carbinolamine dehydratase/dimerization cofactor of HNF1. DNA Cell Biol. 18: 243-252, 1999. [PubMed: 10098606] [Full Text: https://doi.org/10.1089/104454999315466]
Mendel, D. B., Khavari, P. A., Conley, P. B., Graves, M. K., Hansen, L. P., Admon, A., Crabtree, G. R. Characterization of a cofactor that regulates dimerization of a mammalian homeodomain protein. Science 254: 1762-1767, 1991. [PubMed: 1763325] [Full Text: https://doi.org/10.1126/science.1763325]
Milatovich, A., Mendel, D. B., Crabtree, G. R., Francke, U. Genes for the dimerization cofactor of hepatocyte nuclear factor-1-alpha (DCOH) are on human and murine chromosomes 10. Genomics 16: 292-295, 1993. [PubMed: 8486378] [Full Text: https://doi.org/10.1006/geno.1993.1182]
Simaite, D., Kofent, J., Gong, M., Ruschendorf, F., Jia, S., Arn, P., Bentler, K., Ellaway, C., Kuhnen, P., Hoffmann, G. F., Blau, N., Spagnoli, F. M., Hubner, N., Raile, K. Recessive mutations in PCBD1 cause a new type of early-onset diabetes. Diabetes 63: 3557-3564, 2014. [PubMed: 24848070] [Full Text: https://doi.org/10.2337/db13-1784]
Thony, B., Heizmann, C. W., Mattei, M.-G. Chromosomal location of two human genes encoding tetrahydrobiopterin-metabolizing enzymes: 6-pyruvoyltetrahydropterin synthase maps to 11q22.3-q23.3, and pterin-4-alpha-carbinolamine dehydratase maps to 10q22. Genomics 19: 365-368, 1994. [PubMed: 8188266] [Full Text: https://doi.org/10.1006/geno.1994.1071]
Thony, B., Neuheiser, E., Kierat, L., Rolland, M. O., Guibaud, P., Schluter, T., Germann, R., Heidenreich, R. A., Duran, M., de Klerk, J. B. C., Ayling, J. E., Blau, N. Mutations in the pterin-4-alpha-carbinolamine dehydratase (PCBD) gene cause a benign form of hyperphenylalaninemia. Hum. Genet. 103: 162-167, 1998. [PubMed: 9760199] [Full Text: https://doi.org/10.1007/s004390050800]
Thony, B., Neuheiser, F., Blau, N., Heizmann, C. W. Characterization of the human PCBD gene encoding the bifunctional protein pterin-4-alpha-carbinolamine dehydrase/dimerization cofactor for the transcription factor HNF-1-alpha. Biochem. Biophys. Res. Commun. 210: 966-973, 1995. [PubMed: 7763270] [Full Text: https://doi.org/10.1006/bbrc.1995.1751]
Thony, B., Neuheiser, F., Kierat, L., Blaskovics, M., Arn, P. H., Ferreira, P., Rebrin, I., Ayling, J., Blau, N. Hyperphenylalaninemia with high levels of 7-biopterin is associated with mutations in the PCBD gene encoding the bifunctional protein pterin-4a-carbinolamine dehydratase and transcriptional coactivator (DCoH). Am. J. Hum. Genet. 62: 1302-1311, 1998. [PubMed: 9585615] [Full Text: https://doi.org/10.1086/301887]