TNAP: A New Multitask Enzyme in Energy Metabolism

Briolay, Anne; Bessueille, Laurence; Magne, David

doi:10.3390/ijms221910470

Cited by 14 publications

(8 citation statements)

References 101 publications

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“…TNAP is a multifunction, multi-site enzyme with broad dephosphorylating activity, including the conversion of the hydrophilic form of vitamin B6 pyridoxal-5 0 -phosphate into pyridoxal, which can cross the blood-brain barrier into the central nervous system (CNS). [22][23][24] Among its functions in the CNS, pyridoxal acts as a co-factor for glutamate decarboxylase, which synthesizes γ-aminobutyric acid (GABA), one of the main inhibitory neurotransmitters in the CNS, from glutamate; decreased GPI-anchored TNAP, therefore, has been suggested to lead to GABA deficiency, contributing to the pathogenesis of epilepsy in patients with GPI-anchor deficiencies. 12,23 In the clinical setting, this hypothesis was tested by pyridoxine supplementation for seizure control in patients with different GPI-anchor biosynthesis disorders, with clinical and electrographic response achieved in some individuals.…”

Section: Discussionmentioning

confidence: 99%

“…One of the main theories focuses on the role of decreased activity of GPI‐anchored alkaline phosphatases, especially tissue nonspecific alkaline phosphatase (TNAP). TNAP is a multi‐function, multi‐site enzyme with broad dephosphorylating activity, including the conversion of the hydrophilic form of vitamin B6 pyridoxal‐5′‐phosphate into pyridoxal, which can cross the blood–brain barrier into the central nervous system (CNS) 22–24 . Among its functions in the CNS, pyridoxal acts as a co‐factor for glutamate decarboxylase, which synthesizes γ‐aminobutyric acid (GABA), one of the main inhibitory neurotransmitters in the CNS, from glutamate; decreased GPI‐anchored TNAP, therefore, has been suggested to lead to GABA deficiency, contributing to the pathogenesis of epilepsy in patients with GPI‐anchor deficiencies 12,23 .…”

Section: Discussionmentioning

confidence: 99%

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PIGO‐CDG: A case study with a new genotype, expansion of the phenotype, literature review, and nosological considerations

Starosta,

Kerashvili,

Pruitt

et al. 2023

JIMD Reports

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The phosphatidylinositol glycan anchor biosynthesis class O protein (PIGO) enzyme is an important step in the biosynthesis of glycosylphosphatidylinositol (GPI), which is essential for the membrane anchoring of several proteins. Bi‐allelic pathogenic variants in PIGO lead to a congenital disorder of glycosylation (CDG) characterized by global developmental delay, an increase in serum alkaline phosphatase levels, congenital anomalies including anorectal, genitourinary, and limb malformations in most patients; this phenotype has been alternately called “Mabry syndrome” or “hyperphosphatasia with impaired intellectual development syndrome 2.” We report a 22‐month‐old female with PIGO deficiency caused by novel PIGO variants. In addition to the Mabry syndrome phenotype, our patient's clinical picture was complicated by intermittent hypoglycemia with signs of functional hyperinsulinism, severe secretory diarrhea, and osteopenia with a pathological fracture, thus, potentially expanding the known phenotype of this disorder, although more studies are necessary to confirm these associations. We also provide an updated review of the literature, and propose unifying the nomenclature of PIGO deficiency as “PIGO‐CDG,” which reflects its pathophysiology and position in the broad scope of metabolic disorders and congenital disorders of glycosylation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

PIGO‐CDG: A case study with a new genotype, expansion of the phenotype, literature review, and nosological considerations

Starosta,

Kerashvili,

Pruitt

et al. 2023

JIMD Reports

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“…TNAP enzyme replacement targets to mineralized tissues. It remains unknown if a TNAP function in non-mineralized tissues is responsible for the diminished body size seen in TNAP deficient mice and patients but recent studies indicate that TNAP does play a role in cell and body metabolism including brown fat thermogenesis (4,41,50).…”

Section: Discussionmentioning

confidence: 99%

“…In humans and mice, TNAP is expressed in bone, growth plate cartilage, teeth, brain, kidney and liver (1)(2)(3). While the function(s) of TNAP in liver, kidney and brain are still being established (4)(5)(6)(7), numerous prior studies have established that TNAP is an essential promoter of tissue mineralization when co-expressed with type I collagen in mineralized tissues (8)(9)(10)(11). The primary known function of TNAP in tissue mineralization is to promote calcium phosphate hydroxyapatite crystal growth in pre-mineralized cartilaginous matrix (osteoid) by decreasing levels of the mineralization inhibitor, inorganic pyrophosphate, and by dephosphorylating osteopontin (12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Deletion of the Pyrophosphate Generating Enzyme ENPP1 Rescues Craniofacial Abnormalities in the TNAP−/− Mouse Model of Hypophosphatasia and Reveals FGF23 as a Marker of Phenotype Severity

2022

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Hypophosphatasia is a rare heritable metabolic disorder caused by deficient Tissue Non-specific Alkaline Phosphatase (TNAP) enzyme activity. A principal function of TNAP is to hydrolyze the tissue mineralization inhibitor pyrophosphate. ENPP1 (Ectonucleotide Pyrophosphatase/Phosphodiesterase 1) is a primary enzymatic generator of pyrophosphate and prior results showed that elimination of ENPP1 rescued bone hypomineralization of skull, vertebral and long bones to different extents in TNAP null mice. Current TNAP enzyme replacement therapy alleviates skeletal, motor and cognitive defects but does not eliminate craniosynostosis in pediatric hypophosphatasia patients. To further understand mechanisms underlying craniosynostosis development in hypophosphatasia, here we sought to determine if craniofacial abnormalities including craniosynostosis and skull shape defects would be alleviated in TNAP null mice by genetic ablation of ENPP1. Results show that homozygous deletion of ENPP1 significantly diminishes the incidence of craniosynostosis and that skull shape abnormalities are rescued by hemi- or homozygous deletion of ENPP1 in TNAP null mice. Skull and long bone hypomineralization were also alleviated in TNAP−/−/ENPP1−/− compared to TNAP−/−/ENPP1+/+ mice, though loss of ENPP1 in combination with TNAP had different effects than loss of only TNAP on long bone trabeculae. Investigation of a relatively large cohort of mice revealed that the skeletal phenotypes of TNAP null mice were markedly variable. Because FGF23 circulating levels are known to be increased in ENPP1 null mice and because FGF23 influences bone, we measured serum intact FGF23 levels in the TNAP null mice and found that a subset of TNAP−/−/ENPP1+/+ mice exhibited markedly high serum FGF23. Serum FGF23 levels also correlated to mouse body measurements, the incidence of craniosynostosis, skull shape abnormalities and skull bone density and volume fraction. Together, our results demonstrate that balanced expression of TNAP and ENPP1 enzymes are essential for microstructure and mineralization of both skull and long bones, and for preventing craniosynostosis. The results also show that FGF23 rises in the TNAP−/− model of murine lethal hypophosphatasia. Future studies are required to determine if the rise in FGF23 is a cause, consequence, or marker of disease phenotype severity.

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“…Mutations in the genes coding for the previously listed proteins may cause a mineralization disorder, usually diagnosed in infancy, at least in its severe forms [ 17 ]. Among these disorders, hypophosphatasia, the genetic metabolic disorder characterized by reduced activity of serum ALP, is one of the most notable [ 18 ]. Some individuals, often heterozygous for tissue non-specific alkaline phosphatase mutation ( TNSALP ), may manifest an abnormal mineralization only in adult age, mimicking acquired forms of mineralization defect, which have to be considered in the differential diagnosis [ 19 ].…”

Section: Physiopathology Of Defective Mineralization and Proposed Pat...mentioning

confidence: 99%

Osteomalacia Is Not a Single Disease

Cianferotti

2022

IJMS

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Among bone-material qualities, mineralization is pivotal in conferring stiffness and toughness to the bone. Osteomalacia, a disease ensuing from inadequate mineralization of the skeleton, is caused by different processes leading to decreased available mineral (calcium and/or phosphate) or enzymatic alterations. Vitamin D deficiency, which remains the major cause of altered mineralization leading to inadequate intestinal calcium and phosphate absorption, may be also associated with other conditions primarily responsible for abnormal mineralization. Given the reality of widespread vitamin D inadequacy, a full biochemical assessment of mineral metabolism is always necessary to rule out or confirm other conditions. Both too-high or too-low serum alkaline phosphatase (ALP) levels are important for diagnosis. Osteomalacic syndrome is reversible, at least in part, by specific treatment. Osteomalacia and bone mineralization themselves constitute largely unexplored fields of research. The true prevalence of the different forms of osteomalacia and the recovery after proper therapy have yet to be determined in the real world. Although non-invasive techniques to assess bone mineralization are not available in clinical practice, the systematic assessment of bone quality could help in refining the diagnosis and guiding the treatment. This review summarizes what is known of osteomalacia recent therapeutic developments and highlights the future issues of research in this field.

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TNAP: A New Multitask Enzyme in Energy Metabolism

Cited by 14 publications

References 101 publications

PIGO‐CDG: A case study with a new genotype, expansion of the phenotype, literature review, and nosological considerations

PIGO‐CDG: A case study with a new genotype, expansion of the phenotype, literature review, and nosological considerations

Deletion of the Pyrophosphate Generating Enzyme ENPP1 Rescues Craniofacial Abnormalities in the TNAP−/− Mouse Model of Hypophosphatasia and Reveals FGF23 as a Marker of Phenotype Severity

Osteomalacia Is Not a Single Disease

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