|Mutation Type||splice site|
|Coordinate||158,782,403 bp (GRCm38)|
|Base Change||A ⇒ T (forward strand)|
|Gene Name||pappalysin 2|
|Synonym(s)||pregnancy-associated plasma preproprotein-A2, placenta-specific 3, pregnancy-associated plasma protein-E, PAPP-A2, PLAC3, Pappe|
|Chromosomal Location||158,711,727-158,980,490 bp (-)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a member of the pappalysin family of metzincin metalloproteinases. The encoded protein cleaves insulin-like growth factor-binding protein 5 and is thought to be a local regulator of insulin-like growth factor (IGF) bioavailability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2010]
PHENOTYPE: Mice homozygous for a null mutation are viable and fertile but display postnatal growth retardation that is more pronounced in females compared to males. [provided by MGI curators]
|Amino Acid Change|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000124022]|
|Predicted Effect||probably null|
|Predicted Effect||probably null|
|Meta Mutation Damage Score||0.6616|
|Is this an essential gene?||Non Essential (E-score: 0.000)|
|Candidate Explorer Status||CE: excellent candidate; human score: 0; ML prob: 0.506|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Last Updated||2019-01-29 1:43 PM by Diantha La Vine|
|Record Created||2017-09-11 10:26 AM|
The lilliputian3 phenotype was identified among G3 mice of the pedigree R5278, some of which showed reduced body weights compared to wild-type littermates (Figure 1).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 53 mutations. The body weight phenotype was linked to a mutation in Pappa2: a T to A transversion at base pair 158,782,403 (v38) on chromosome 1, or base pair 198,125 in the GenBank genomic region NC_000067 within intron 15 (nine base pairs from exon 16). Linkage was found with a recessive model of inheritance (P = 0.000255), wherein two variant homozygotes departed phenotypically from 24 homozygous reference mice and 21 heterozygous mice (Figure 2).
The effect of the mutation at the cDNA and protein levels has not been examined, but the mutation is predicted to result in the use of a cryptic site in intron 15. The resulting transcript would have a 7-base pair insertion of intron 15, which would cause a frame-shifted protein product beginning after amino acid 1,499 of the protein and premature termination after the inclusion of 10 aberrant amino acids.
The acceptor splice site of intron 15, which is destroyed by the lilliputian3 mutation, is indicated in blue lettering and the mutated nucleotide is indicated in red.
Pappa2 encodes pregnancy-associated plasma protein A2 (PAPP-A2; alternatively, PAPP-E), a member of the pappalysin group of the metzincin protease family along with PAPP-A and ulilysin. PAPP-A2 is a 1,789-amino acid protein that has several domains: a signaling peptide (amino acids 1-18), a laminin G-like domain (amino acids 271-440), a peptidase/proteolytic domain (amino acids 669-832), a fibronectin 3-like domain (FN3; amino acids 844-1103), four complement control protein (CCP) domains (alternatively, short consensus repeat (SCR); amino acids 1394-1457, 1462-1519, 1523-1588, and 1593-1644), and two Lin12/Notch repeats (LNRs; amino acids 572-614 and 1720-1757) (Figure 3) (1).
The mutation in lilliputian3 results in frame-shifted protein product beginning after amino acid 1,499 of the protein and premature termination after the inclusion of 10 aberrant amino acids. Amino acid 1,499 is within the second CCP domain.
Please see the record Lilliputian for more information about Pappa2.
PAPP-A2 is a protease that acts on insulin-like growth factor binding protein 5 (IGFBP5), a factor involved in bone metabolism (2;3) and IGFBP3 (4). IGFBP5 regulates the IGF-I signaling pathways by binding IGF-I. IGFBP5 also has IGF-I-independent functions. IGFPB5 is able to bind its putative receptor to enter the cytoplasm and subsequently interact with, and regulate, other proteins. Studies have shown that PAPP-A2 has roles in human pregnancy (5), reproductive traits in cattle (6), and postnatal growth in mice (7;8). Pappa2-deficient (Pappa2-/-) mice are viable and smaller than wild-type mice (8). At 3-18 weeks of age, the male Pappa2-/- mice had approximately 10% lower body weights than that in age-matched wild-type mice (8). Weight reduction was more pronounced in female mice compared to that in age-matched male mice (8). In the female mice, all organs except ovaries were larger than that in wild-type mice. The Pappa2-/- mice have shorter femur length than that in wild-type mice, but do not exhibit changes in bone mineral density. Pappa2 deletion does not affect placental or embryonic mass at embryonic day 12.5 (9). At birth, the Pappa2-/- mice exhibited a trend towards lower birth mass (9). At 3, 6, and 10 weeks of age, the Pappa2-/- mice exhibited reduced body mass and tail lengths compared to wild-type mice (9). The shape of the pelvic girdle significantly differed between that in the Pappa2-/- and wild-type mice; the Pappa2-/- mice had a more feminine shape and was disproportionately small (9). Matings between Pappa2-/- mice exhibited a delay to first litter, increased number of days between litter, and a reduced number of pups per litter compared to matings between wild-type mice (8). Although Pappa2 deletion results in diminished levels of circulating IGF-I, IGFBP-3, and IGFBP-5, there were no glucose metabolism phenotypes observed (10). In addition, loss of Pappa2 expression did not result in weight gain or adiposity on a high-fat diet (10). Loss of Pappa2 expression in mouse does not effect female fertility, but has subtle effects on male fertility (11). The body weight phenotype of the lilliputian3 mice indicates loss-of-function of PAPP-A2lilliputian3.
lilliputian3(F):5'- ACAGGAACACTCACTTCTTGC -3'
lilliputian3(R):5'- ACCTCACTGAGAACTGTAGAGTAAG -3'
lilliputian3_seq(F):5'- ACATAGTAGCCTGGTTTGCAC -3'
lilliputian3_seq(R):5'- TCCACATAGGAGGGAGAT -3'
1. Farr, M., Strube, J., Geppert, H. G., Kocourek, A., Mahne, M., and Tschesche, H. (2000) Pregnancy-Associated Plasma Protein-E (PAPP-E). Biochim Biophys Acta. 1493, 356-362.
2. Conover, C. A. (2008) Insulin-Like Growth Factor-Binding Proteins and Bone Metabolism. Am J Physiol Endocrinol Metab. 294, E10-4.
3. Govoni, K. E., Baylink, D. J., and Mohan, S. (2005) The Multi-Functional Role of Insulin-Like Growth Factor Binding Proteins in Bone. Pediatr Nephrol. 20, 261-268.
4. Overgaard, M. T., Boldt, H. B., Laursen, L. S., Sottrup-Jensen, L., Conover, C. A., and Oxvig, C. (2001) Pregnancy-Associated Plasma Protein-A2 (PAPP-A2), a Novel Insulin-Like Growth Factor-Binding Protein-5 Proteinase. J Biol Chem. 276, 21849-21853.
5. Yan, X., Baxter, R. C., and Firth, S. M. (2010) Involvement of Pregnancy-Associated Plasma Protein-A2 in Insulin-Like Growth Factor (IGF) Binding Protein-5 Proteolysis during Pregnancy: A Potential Mechanism for Increasing IGF Bioavailability. J Clin Endocrinol Metab. 95, 1412-1420.
6. Wickramasinghe, S., Rincon, G., and Medrano, J. F. (2011) Variants in the Pregnancy-Associated Plasma Protein-A2 Gene on Bos Taurus Autosome 16 are Associated with Daughter Calving Ease and Productive Life in Holstein Cattle. J Dairy Sci. 94, 1552-1558.
7. Christians, J. K., Hoeflich, A., and Keightley, P. D. (2006) PAPPA2, an Enzyme that Cleaves an Insulin-Like Growth-Factor-Binding Protein, is a Candidate Gene for a Quantitative Trait Locus Affecting Body Size in Mice. Genetics. 173, 1547-1553.
8. Conover, C. A., Boldt, H. B., Bale, L. K., Clifton, K. B., Grell, J. A., Mader, J. R., Mason, E. J., and Powell, D. R. (2011) Pregnancy-Associated Plasma Protein-A2 (PAPP-A2): Tissue Expression and Biological Consequences of Gene Knockout in Mice. Endocrinology. 152, 2837-2844.
9. Christians, J. K., de Zwaan, D. R., and Fung, S. H. (2013) Pregnancy Associated Plasma Protein A2 (PAPP-A2) Affects Bone Size and Shape and Contributes to Natural Variation in Postnatal Growth in Mice. PLoS One. 8, e56260.
10. Christians, J. K., Bath, A. K., and Amiri, N. (2015) Pappa2 Deletion Alters IGFBPs but has Little Effect on Glucose Disposal Or Adiposity. Growth Horm IGF Res. 25, 232-239.
|Science Writers||Anne Murray|
|Illustrators||Diantha La Vine|
|Authors||Emre Turer and Bruce Beutler|