A novel mutation in the <i>HPGD</i> gene causing primary hypertrophic osteoarthropathy with digital clubbing in a Pakistani family

Khan, Anwar; Muhammad, Noor; Khan, Sher Alam; Ullah, Waheed; Nasır, Abdul; Afzal, Sibtain; Ramzan, Khushnooda; Basit, Sulman; Khan, Saadullah

doi:10.1111/ahg.12239

Cited by 9 publications

(3 citation statements)

References 16 publications

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“…The HPGD gene encodes a helical protein, consists of 266 amino acids, which belongs to the member of the short-chain dehydrogenase family (SDR) family (31). Generally, SDRs are divided into two larger families, ‘classical’ with 250-odd residues and ‘extended’ with 350-odd residues.…”

Section: Discussionmentioning

confidence: 99%

The first case of primary hypertrophic osteoarthropathy with soft tissue giant tumors caused by HPGD loss-of-function mutation

Pang

et al. 2019

Endocrine Connections

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Background Primary hypertrophic osteoarthropathy (PHO) is a rare genetic multi-organic disease characterized by digital clubbing, periostosis and pachydermia. Two genes, HPGD and SLCO2A1, which encodes 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and prostaglandin transporter (PGT), respectively, have been reported to be related to PHO. Deficiency of aforementioned two genes leads to failure of prostaglandin E2 (PGE2) degradation and thereby elevated levels of PGE2. PGE2 plays an important role in tumorigenesis. Studies revealed a tumor suppressor activity of 15-PGDH in tumors, such as lung, bladder and breast cancers. However, to date, no HPGD-mutated PHO patients presenting concomitant tumor has been documented. In the present study, we reported the first case of HPGD-mutated PHO patient with soft tissue giant tumors at lower legs and evaluated the efficacy of selective COX-2 inhibitor (etoricoxib) treatment in the patient. Methods In this study, we summarized the clinical data, collected the serum and urine samples for biochemical test and analyzed the HPGD gene in our patient. Results A common HPGD mutation c.310_311delCT was identified in the patient. In addition to typical clinical features (digital clubbing, periostosis and pachydermia), the patient demonstrated a new clinical manifestation, a giant soft tissue tumor on the left lower leg which has not been reported in HPGD-mutated PHO patient before. After 6-month treatment with etoricoxib, the patient showed decreased PGE2 levels and improved PHO-related symptoms. Though the soft tissue tumor persisted, it seemed to be controlled under the etoricoxib treatment. Conclusion This finding expanded the clinical spectrum of PHO and provided unique insights into the HPGD-mutated PHO.

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Section: Discussionmentioning

confidence: 99%

The first case of primary hypertrophic osteoarthropathy with soft tissue giant tumors caused by HPGD loss-of-function mutation

Pang

et al. 2019

Endocrine Connections

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“…We reviewed all PHOAR1 cases reported so far. A total of 77 cases have been reported to date since HPGD mutations in PHO patients were first identified by Uppal et al in 2008 [5,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]. We summarized the clinical manifestations of all PHOAR1 patients reported in Table 3.…”

Section: Discussionmentioning

confidence: 99%

Clinical and biochemical characteristics of 12 Chinese primary hypertrophic osteoarthropathy patients with HPGD mutations

Lu¹,

Xu²,

Li³

et al. 2022

Int. J. Biol. Sci.

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Primary hypertrophic osteoarthropathy (PHO) is a rare genetic disease mainly affecting the skeletal and skin. Two genes involved in prostaglandin degradation are known to be responsible for PHO: HPGD and SLCO2A1. HPGD gene mutation can cause PHO autosomal recessive 1 (PHOAR1). The purpose of the present study is to analyze the clinical and biochemical characteristics and HPGD gene mutations of 12 Chinese PHOAR1 patients. Twelve PHOAR1 patients from eleven families, including eleven males and one female, were enrolled in this study. Digital clubbing and periostosis came out to be the most common features, which always occur in the early childhood. We performed HPGD gene analysis and identified six novel (c.1A>G, c.34G>T, c.317T>A, c.475G>T, c.548C>T and c.421+1G>T) and one known (c.310_311delCT) HPGD mutations. The recurrent mutation c.310_311delCT were found in all eleven patients, suggesting it is a hotspot mutation. PHOAR1 patients are considered to have an autosomal recessive inheritance pattern. Here, in addition to nine compound heterozygous patients and two homozygous patients, we found one heterozygous patient and reviewed two heterozygous patients reported in other studies. In terms of biochemical characteristics, our PHOAR1 patients have elevated urinary prostaglandin E2 (PGE2) levels (P<0.001) and decreased urinary prostaglandin E metabolite (PGE-M) levels (P=0.04) compared with healthy controls. The patients' PGE2/PGE-M (E/M) ratio came out to be lower than normal subjects (P<0.001). This study provides a comprehensive description of the clinical phenotypes of Chinese PHOAR1 patients and expands the genotypic spectrum of the disease.

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“…As explained above, the inhibitors reported in the literature bind to the substrate binding site sharing interactions with those predicted for Meridianin-A. HPGD is implicated in digital clubbing [122,123], a disorder that is associated with several disorders, such as cardiovascular disease or cancer [124]. The modulators reported in the literature are aimed at inhibiting this enzyme, as HPGD is the key enzyme for the inactivation of prostaglandins, and thus regulates processes such as inflammation or proliferation [92].…”

Section: Binding Mode Analysis Molecular Mechanics/generalized Born Surface Area (Mm/gbsa) Overall Molecule-target Associationmentioning

confidence: 99%

Computer-Aided Drug Design (CADD) to De-Orphanize Marine Molecules: Finding Potential Therapeutic Agents for Neurodegenerative and Cardiovascular Diseases

Llorach-Parés

Nonell-Canals²,

Ávila

et al. 2022

Marine Drugs

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Computer-aided drug design (CADD) techniques allow the identification of compounds capable of modulating protein functions in pathogenesis-related pathways, which is a promising line on drug discovery. Marine natural products (MNPs) are considered a rich source of bioactive compounds, as the oceans are home to much of the planet’s biodiversity. Biodiversity is directly related to chemodiversity, which can inspire new drug discoveries. Therefore, natural products (NPs) in general, and MNPs in particular, have been used for decades as a source of inspiration for the design of new drugs. However, NPs present both opportunities and challenges. These difficulties can be technical, such as the need to dive or trawl to collect the organisms possessing the compounds, or biological, due to their particular marine habitats and the fact that they can be uncultivable in the laboratory. For all these difficulties, the contributions of CADD can play a very relevant role in simplifying their study, since, for example, no biological sample is needed to carry out an in-silico analysis. Therefore, the amount of natural product that needs to be used in the entire preclinical and clinical study is significantly reduced. Here, we exemplify how this combination between CADD and MNPs can help unlock their therapeutic potential. In this study, using a set of marine invertebrate molecules, we elucidate their possible molecular targets and associated therapeutic potential, establishing a pipeline that can be replicated in future studies.

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A novel mutation in the HPGD gene causing primary hypertrophic osteoarthropathy with digital clubbing in a Pakistani family

Cited by 9 publications

References 16 publications

The first case of primary hypertrophic osteoarthropathy with soft tissue giant tumors caused by HPGD loss-of-function mutation

The first case of primary hypertrophic osteoarthropathy with soft tissue giant tumors caused by HPGD loss-of-function mutation

Clinical and biochemical characteristics of 12 Chinese primary hypertrophic osteoarthropathy patients with HPGD mutations

Computer-Aided Drug Design (CADD) to De-Orphanize Marine Molecules: Finding Potential Therapeutic Agents for Neurodegenerative and Cardiovascular Diseases

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