Alternative titles; symbols
HGNC Approved Gene Symbol: HPGD
SNOMEDCT: 239055005, 720753002;
Cytogenetic location: 4q34.1 Genomic coordinates (GRCh38): 4:174,490,175-174,522,893 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q34.1 | ?Digital clubbing, isolated congenital | 119900 | Autosomal recessive | 3 |
| Cranioosteoarthropathy | 259100 | Autosomal recessive | 3 | |
| Hypertrophic osteoarthropathy, primary, autosomal recessive 1 | 259100 | Autosomal recessive | 3 |
Prostaglandins are involved in many physiologic and cellular processes, such as inflammation. Pichaud et al. (1997) noted that the NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH, type I) is the main enzyme of prostaglandin degradation. By catalyzing the conversion of the 15-hydroxyl group of prostaglandins into a keto group, this ubiquitous enzyme strongly reduces the biologic activity of these molecules. The nucleotide sequence coding for PGDH1 was established by Ensor et al. (1990) who found an 801-bp open reading frame coding for a protein with 266 amino acids identical to the amino acid sequence established by Krook et al. (1990).
By human/rodent cell hybrid analysis and isotopic in situ hybridization, Pichaud et al. (1997) mapped the PGDH1 gene to 4q34-q35.
Cortisol reduces the activity of PGDH in human placental cells. 11-beta hydroxysteroid dehydrogenase type II (HSD11B2; 614232) converts cortisol to cortisone. Schoof et al. (2001) investigated a possible correlation between HSD11B2 and PGDH gene expression in the placenta of patients with preeclampsia. They concluded that, in preeclampsia, HSD11B2 mRNA expression is reduced, leading to a decrease of HSD11B2 activity. Furthermore, by means of an autocrine or paracrine mechanism, the diminished conversion of placental cortisol may lead to reduced PGDH mRNA expression.
Primary Hypertrophic Osteoarthropathy, Autosomal Recessive
Uppal et al. (2008) identified 2 different homozygous truncating mutations in the HPGD gene (601688.0002, 601688.0003) in affected members of 2 unrelated families with autosomal recessive primary hypertrophic osteoarthropathy (PHOAR1; 259100). Affected individuals from 2 additional families with cranioosteoarthropathy, a variant of PHO, had a missense mutation in the HPGD gene (601688.0001). Clinical features included digital clubbing, periostosis, and variable pachydermia. All homozygous affected individuals had significantly increased urinary prostaglandin E2 (PGE2) levels, up to more than 7 times control values. Heterozygous family members had mild digital clubbing that was most apparent in older individuals, suggesting that the carrier state for HPGD mutations results in a modest, chronic elevation of circulating prostaglandin and late-onset clubbing. Four of the 13 HPGD-deficient patients had a persistent patent ductus arteriosus (PDA), which likely resulted from increased PGE2. However, most did not have patent ductus arteriosus, suggesting that HPGD is not absolutely required for ductus closure in humans.
In affected members of 3 unrelated consanguineous Turkish families with primary hypertrophic osteoarthropathy, Yuksel-Konuk et al. (2009) identified homozygosity for missense mutations in the HPGD gene: A140P (601688.0001) in 2 of the families, and M1L (601688.0005) in the third family.
In a sister and brother from a consanguineous Turkish family with primary hypertrophic osteoarthropathy, Erken et al. (2015) identified homozygosity for a 2-bp deletion in the HPGD gene (601688.0006).
In 4 boys from 3 unrelated Indian families with PHOAR1, Radhakrishnan et al. (2020) identified homozygous mutations in the HPGD gene: the previously identified A140P mutation and 2 novel mutations (G12S, 601688.0007; Q105X, 601688.0008). The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in 2 families; in 1 family, a paternal sample was not available for study.
Digital Clubbing, Isolated Congenital
In a 6-generation consanguineous Pakistani family with isolated congenital digital clubbing (DIGC; 119900) mapping to chromosome 4q32.3, Tariq et al. (2009) sequenced 10 candidate genes and identified homozygosity for a missense mutation in the HPGD gene (S193P; 601688.0004) in affected individuals. Obligate carriers were heterozygous for the mutation, which was not found in 300 ethnically matched chromosomes. The authors stated that aside from nail clubbing, none of the clinical features associated with primary hypertrophic osteoarthropathy were found in affected members of this family, and clubbing was not seen in heterozygous carriers, as is the case in PHO families.
Coggins et al. (2002) generated mice deficient in Pgdh by targeted disruption. The Pgdh -/- pups died between 12 and 48 hours of life because of patent ductus arteriosus (see 607411) leading to congestive heart failure. Treatment with indomethacin rescued the phenotype. Coggins et al. (2002) concluded that alterations in PGE2 metabolism by PGDH during the perinatal period is essential for the permanent closure of the ductus arteriosus.
In affected members of 2 consanguineous Pakistani families with autosomal recessive cranioosteoarthropathy (see 259100), Uppal et al. (2008) identified a homozygous 418G-C transversion in exon 4 of the HPGD gene, resulting in an ala140-to-pro (A140P) substitution. Clinical features included infantile onset of swelling of the joints, digital clubbing, hyperhidrosis, delayed closure of the fontanels, periostosis, and variable patent ductus arteriosus. Pachydermia was not a prominent feature. In vitro functional analysis showed that the mutant protein had no detectable activity. Modeling suggested that the mutation disrupts the binding of the substrate prostaglandin E. The mutation was not identified in 100 control individuals of Pakistani origin. One of the families had been reported by Sinha et al. (1997) and the other by Dabir et al. (2007).
In 3 affected individuals from 2 unrelated Turkish families with primary hypertrophic osteoarthropathy (PHOAR1; 259100), Yuksel-Konuk et al. (2009) identified homozygosity for the A140P mutation in the HPGD gene. The mutation segregated with disease in both families and was not found in 100 controls. The 2 families originated from different cities and denied any relationship; haplotype information was unavailable.
In a 3-year-old boy (patient 2), born to consanguineous Indian parents, with PHOAR1, Radhakrishnan et al. (2020) identified homozygosity for the A140P mutation in the HPGD gene. The mother was a carrier for the mutation, but the father was not tested. Functional studies were not performed.
In a mother and daughter with autosomal recessive primary hypertrophic osteoarthropathy-1 (PHOAR1; 259100), Uppal et al. (2008) identified a homozygous deletion/insertion mutation in exon 3 of the HPGD gene (232_241delinsCA), resulting in a frameshift, premature termination, and deletion of the entire prostaglandin E2-binding domain. The unaffected father was heterozygous for the mutation, and the family was consanguineous, thus showing pseudodominant inheritance.
In affected members of a nonconsanguineous Polish family with primary hypertrophic osteoarthropathy (PHOAR1; 259100) reported by Latos-Bielenska et al. (2007), Uppal et al. (2008) identified a homozygous 2-bp deletion (175delCT) in exon 2 of the HPGD gene, resulting in a frameshift, premature termination, and deletion of the entire prostaglandin E2-binding domain. The patients had infantile onset, delayed closure of the fontanels, digital clubbing, and mild pachydermia and periostosis.
In affected members of a 6-generation consanguineous Pakistani family with isolated congenital digital clubbing (DIGC; 119900), Tariq et al. (2009) identified homozygosity for a 577T-C transition in exon 6 of the HPGD gene, resulting in a ser193-to-pro (S193P) substitution at a conserved residue. Obligate carriers were heterozygous for the mutation, which was not found in 300 ethnically matched chromosomes. Affected individuals had normal skin and sweating, with no bone or joint pain; x-rays of hands and feet showed stubby soft tissue accumulation at terminal phalanges with normal bones and angles, and x-rays of chest, shoulders, elbows, and thorax showed no abnormalities.
In 3 sisters with primary autosomal recessive hypertrophic osteoarthropathy (PHOAR1; 259100), who were born of first-cousin Turkish parents, Yuksel-Konuk et al. (2009) identified homozygosity for a c.1A-T transversion in exon 1 of the HPGD gene, resulting in a met1-to-leu (M1L) substitution at the highly conserved initiation codon. In addition to marked digital clubbing, all 3 sisters had knee joint effusion. The mutation segregated with disease in the family and was not found in 100 controls.
In a sister and brother with primary hypertrophic osteoarthropathy (PHOAR1; 259100) from a consanguineous Turkish family, Erken et al. (2015) identified homozygosity for a 2-bp deletion (c.310_311delCT) in exon 3 of the HPGD gene, causing a frameshift predicted to result in a premature termination codon (Leu104AlafsTer3). The unaffected parents and 5 other unaffected family members were heterozygous for the mutation; examination revealed no signs of the disease in the heterozygous carriers. The mutation was not found in 136 Turkish controls, showing with at least 80% probability that the deletion was not a common variant in the Turkish population.
In a 6-year-old boy (patient 1), born to consanguineous Indian parents, with primary autosomal recessive hypertrophic osteoarthropathy-1 (PHOAR1; 259100), Radhakrishnan et al. (2020) identified homozygosity for a c.34G-A transition (c.34G-A, NM_000860.5) in exon 1 of the HPGD gene, resulting in a gly12-to-ser (G12S) substitution in a region conserved across species. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. Functional studies were not reported.
In 2 brothers (patients 3 and 4), born to consanguineous Indian parents, with primary autosomal recessive hypertrophic osteoarthropathy-1 (PHOAR1; 259100), Radhakrishnan et al. (2020) identified homozygosity for a c.313C-T transition (c.313C-T, NM_000860.5) in exon 3 of the HPGD gene, resulting in a gln105-to-ter (Q105X) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. Functional studies were not reported.
Coggins, K. G., Latour, A., Nguyen, M. S., Audoly, L., Coffman, T. M., Koller, B. H. Metabolism of PGE2 by prostaglandin dehydrogenase is essential for remodeling the ductus arteriosus. (Letter) Nature Med. 8: 91-92, 2002. [PubMed: 11821873] [Full Text: https://doi.org/10.1038/nm0202-91]
Dabir, T., Sills, A. M., Hall, C. M., Bennett, C., Wilson, L. C., Hennekam, R. C. M. Cranio-osteoarthropathy in sibs. Clin. Dysmorph. 16: 197-201, 2007. [PubMed: 17551338] [Full Text: https://doi.org/10.1097/MCD.0b013e32801470d8]
Ensor, C. M., Yang, J. Y., Okita, R. T., Tai, H. H. Cloning and sequence analysis of the cDNA for human placental NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase. J. Biol. Chem. 265: 14888-14891, 1990. [PubMed: 1697582]
Erken, E., Koroglu, C., Yildiz, F., Ozer, H. T. E., Gulek, B., Tolun, A. A novel recessive 15-hydroxyprostaglandin dehydrogenase mutation in a family with primary hypertrophic osteoarthropathy. Mod. Rheum. 25: 315-321, 2015. [PubMed: 24533558] [Full Text: https://doi.org/10.3109/14397595.2013.874757]
Krook, M., Marekov, L., Jornvall, H. Purification and structural characterization of placental NAD(+)-linked 15-hydroxyprostaglandin dehydrogenase: the primary structure reveals the enzyme to belong to the short-chain alcohol dehydrogenase family. Biochemistry 29: 738-743, 1990. [PubMed: 2337593] [Full Text: https://doi.org/10.1021/bi00455a021]
Latos-Bielenska, A., Marik, I., Kuklik, M., Materna-Kiryluk, A., Povysil, C., Kozlowski, K. Pachydermoperiostosis--critical analysis with report of five unusual cases. Europ. J. Pediat. 166: 1237-1243, 2007. [PubMed: 17285282] [Full Text: https://doi.org/10.1007/s00431-006-0407-6]
Pichaud, F., Delage-Mourroux, R., Pidoux, E., Jullienne, A., Rousseau-Merck, M.-F. Chromosomal localization of the type-I 15-PGDH gene to 4q34-q35. Hum. Genet. 99: 279-281, 1997. [PubMed: 9048936] [Full Text: https://doi.org/10.1007/s004390050354]
Radhakrishnan, P., Jacob, P., Nayak, S. S., Gowrishankar, K., Soni, J. P., Shukla, A., Girisha, K. M. Digital clubbing as the predominant manifestation of hypertrophic osteoarthropathy caused by pathogenic variants in HPGD in three Indian families. Clin. Dysmorph. 29: 123-126, 2020. [PubMed: 32282352] [Full Text: https://doi.org/10.1097/MCD.0000000000000324]
Schoof, E., Girstl, M., Frobenius, W., Kirschbaum, M., Dorr, H. G., Rascher, W., Dotsch, J. Decreased gene expression of 11-beta-hydroxysteroid dehydrogenase type 2 and 15-hydroxyprostaglandin dehydrogenase in human placenta of patients with preeclampsia. J. Clin. Endocr. Metab. 86: 1313-1317, 2001. [PubMed: 11238526] [Full Text: https://doi.org/10.1210/jcem.86.3.7311]
Sinha, G. P., Curtis, P., Haigh, D., Lealman, G. T., Dodds, W., Bennett, C. P. Pachydermoperiostosis in childhood. Brit. J. Rheum. 36: 1224-1227, 1997. [PubMed: 9402870] [Full Text: https://doi.org/10.1093/rheumatology/36.11.1224]
Tariq, M., Azeem, Z., Ali, G., Chishti, M. S., Ahmad, W. Mutation in the HPGD gene encoding NAD+ dependent 15-hydroxyprostaglandin dehydrogenase underlies isolated congenital nail clubbing (ICNC). J. Med. Genet. 46: 14-20, 2009. [PubMed: 18805827] [Full Text: https://doi.org/10.1136/jmg.2008.061234]
Uppal, S., Diggle, C. P., Carr, I. M., Fishwick, C. W. G., Ahmed, M., Ibrahim, G. H., Helliwell, P. S., Latos-Bielenska, A., Phillips, S. E. V., Markham, A. F., Bennett, C. P., Bonthron, D. T. Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy. Nature Genet. 40: 789-793, 2008. Note: Erratum: Nature Genet. 40: 927 only, 2008. [PubMed: 18500342] [Full Text: https://doi.org/10.1038/ng.153]
Yuksel-Konuk, B., Sirmaci, A., Ayten, G. E., Ozdemir, M., Aslan, I., Yilmaz-Turay, U., Erdogan, Y., Tekin, M. Homozygous mutations in the 15-hydroxyprostaglandin dehydrogenase gene in patients with primary hypertrophic osteoarthropathy. Rheum. Int. 30: 39-43, 2009. [PubMed: 19306095] [Full Text: https://doi.org/10.1007/s00296-009-0895-6]