. 2020 Dec 8;10(12):1648. doi: 10.3390/biom10121648

Table 1.

Comparison of ALPL/Alpl/alpl expression and of TNAP/Tnap function in different species.

	Human	Mouse and Rat	Zebrafish and Other Vertebrates
ALPL/Alpl/alpl Expression
Expression database links	The Human Protein Atlas (https://www.proteinatlas.org/ENSG00000162551-ALPL)	Mouse Genome Informatics (http://www.informatics.jax.org/marker/MGI:87983) Rat Genome Database (https://rgd.mcw.edu/rgdweb/report/gene/main.html?id=2100)	Zebrafish Information Network (https://zfin.org/ZDB-GENE-040420-1) Xenopus/Xenbase (http://www.xenbase.org/gene/expression.do?tabId=1&method=displayGenePageExpression&geneId=1010301&objId=1010301) Chicken/Geisha (http://geisha.arizona.edu/geisha/search.jsp?search=NCBI+ID&text=396317)
Embryonic development	Expression of Alpl/alpl has been intensively studied in mice and to a smaller extent in zebrafish, Xenopus and chicken embryos. It has been detected in developing brain regions (telencephalon and diencephalon), bone structures, genital organs, muscle/myotome, kidney, and heart.
Embryonic development	N/A	[197]	[7]
Bone and mineralizing structures	Expression in skeletal bone and other mineralizing structures, e.g., teeth, has been reported for humans and rodents. In addition, expression in limbs/fins has been reported in mice and zebrafish.
Bone and mineralizing structures	[101]	[112]	Expression database
Neurons and brain	Expression in distinct brain regions is common to all vertebrates. Most prominently detected in the forebrain/telencephalon, epiphyses, and layers within the human neocortex.
Neurons and brain	[168]	[158]	[166,167]
Eye	Expression in the retina is reported for a wide number of vertebrates and is evolutionary highly conserved.
Eye	[183]	[183]	[183]
Consequences of TNAP/Tnap Loss of Function
Hypophosphatasia	A large number of disease-causing mutations have been described and result in HPP in humans. Similar disease phenotypes have been reported in knockout and mutated mice, including decreased circulating TNAP levels in blood. Variable severity grades can be observed and result in different pathological disease classes in human patients and murine models.
Hypophosphatasia	[32,33]	[68,70,129]	N/A
Defects in bone and mineralizing structures	Changed levels of TNAP activity result in prominent skeletal and mineralizing defects in humans and mice, e.g., decreased bone density, lack of dentin mineralization, and increased bone resorption. Blocking of Tnap results in a delay of mineralization in zebrafish embryos.
Defects in bone and mineralizing structures	[198,199]	[70,129]	[7]
Defects in teeth	Lack of mineralization results in abnormal tooth development, morphological deformations, and short tooth roots in humans and mice. Observed changes are ALPL/Alpl mutation-dependent.
Defects in teeth	[97,102,103]	[73,98]	N/A
Defects in neurons and Brain	Most prominently, neurological symptoms of HPP patients are seizures, anxiety disorders, and depression. In murine knockout models and heavily affected patients, seizures can be lethal. Although, neuronal tube defects, demonstrated by differences in spine nerve morphology and lumbar nerve roots development, can be abnormal in knockout mice.
Defects in neurons and Brain	[147,164]	[69,146,155]	N/A
Craniosynostosis	Fusion of sutures has been reported in human HPP patients and in knockout mice. However, the phenotype is mutation-dependent and highly variable.
Craniosynostosis	[200]	[72]	N/A
Vascular calcification	HPP patients do not develop vascular calcification, although transgenic mouse models can show pathological arterial calcification.
Vascular calcification	N/A	[201]	N/A

N/A: not available.