Phenotypic Mutation 'Gulliver' (pdf version)
Allele | Gulliver |
Mutation Type |
missense
|
Chromosome | 1 |
Coordinate | 158,684,706 bp (GRCm39) |
Base Change | G ⇒ A (forward strand) |
Gene |
Pappa2
|
Gene Name | pappalysin 2 |
Synonym(s) | PAPP-A2, placenta-specific 3, pregnancy-associated plasma preproprotein-A2, pregnancy-associated plasma protein-E, PLAC3, Pappe |
Chromosomal Location |
158,539,297-158,788,019 bp (-) (GRCm39)
|
MGI Phenotype |
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]
|
Accession Number | NCBI RefSeq: NM_001085376; MGI:3051647
|
Mapped | Yes |
Amino Acid Change |
Threonine changed to Isoleucine
|
Institutional Source | Beutler Lab |
Gene Model |
predicted gene model for protein(s):
[ENSMUSP00000124022 †]
† probably from a misspliced transcript
|
AlphaFold |
E9PZ87 |
SMART Domains |
Protein: ENSMUSP00000124022 Gene: ENSMUSG00000073530 AA Change: T811I
Domain | Start | End | E-Value | Type |
signal peptide
|
1 |
18 |
N/A |
INTRINSIC |
Pfam:Laminin_G_3
|
271 |
440 |
1.2e-25 |
PFAM |
NL
|
572 |
614 |
2.81e-5 |
SMART |
Pfam:Peptidase_M43
|
669 |
832 |
1.5e-12 |
PFAM |
Blast:FN3
|
844 |
1103 |
1e-169 |
BLAST |
low complexity region
|
1130 |
1139 |
N/A |
INTRINSIC |
low complexity region
|
1361 |
1370 |
N/A |
INTRINSIC |
CCP
|
1394 |
1457 |
4.97e0 |
SMART |
CCP
|
1462 |
1519 |
4.81e-1 |
SMART |
CCP
|
1523 |
1588 |
2.58e-4 |
SMART |
CCP
|
1593 |
1644 |
1.13e0 |
SMART |
NL
|
1720 |
1757 |
2.66e-6 |
SMART |
|
Predicted Effect |
probably null
PolyPhen 2
Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
(Using ENSMUST00000159861)
|
Meta Mutation Damage Score |
0.9755 |
Is this an essential gene? |
Non Essential (E-score: 0.000) |
Phenotypic Category |
Unknown |
Candidate Explorer Status |
loading ... |
Single pedigree Linkage Analysis Data
|
|
Penetrance | |
Alleles Listed at MGI | All Mutations and Alleles(9) : Chemically induced (ENU)(3) Chemically induced (other)(2) Targeted(4)
|
Lab Alleles |
Allele | Source | Chr | Coord | Type | Predicted Effect | PPH Score |
IGL01097:Pappa2
|
APN |
1 |
158684718 |
missense |
probably damaging |
1.00 |
IGL01394:Pappa2
|
APN |
1 |
158592674 |
splice site |
probably benign |
|
IGL01570:Pappa2
|
APN |
1 |
158642110 |
nonsense |
probably null |
|
IGL01618:Pappa2
|
APN |
1 |
158684948 |
missense |
probably damaging |
1.00 |
IGL01717:Pappa2
|
APN |
1 |
158684702 |
critical splice donor site |
probably null |
|
IGL01804:Pappa2
|
APN |
1 |
158764089 |
missense |
probably benign |
|
IGL01904:Pappa2
|
APN |
1 |
158611511 |
missense |
probably damaging |
0.99 |
IGL02116:Pappa2
|
APN |
1 |
158672695 |
missense |
probably benign |
0.01 |
IGL02174:Pappa2
|
APN |
1 |
158589188 |
missense |
probably damaging |
1.00 |
IGL02302:Pappa2
|
APN |
1 |
158542571 |
missense |
probably benign |
0.38 |
IGL02422:Pappa2
|
APN |
1 |
158764503 |
missense |
probably damaging |
1.00 |
IGL02572:Pappa2
|
APN |
1 |
158678786 |
missense |
probably benign |
|
IGL02659:Pappa2
|
APN |
1 |
158764364 |
missense |
probably damaging |
0.97 |
IGL02887:Pappa2
|
APN |
1 |
158609829 |
missense |
probably damaging |
1.00 |
IGL02981:Pappa2
|
APN |
1 |
158678714 |
missense |
probably benign |
0.00 |
IGL03128:Pappa2
|
APN |
1 |
158764054 |
missense |
probably benign |
0.16 |
IGL03142:Pappa2
|
APN |
1 |
158682501 |
missense |
probably damaging |
1.00 |
IGL03270:Pappa2
|
APN |
1 |
158592637 |
missense |
possibly damaging |
0.78 |
Fritas
|
UTSW |
1 |
158675533 |
missense |
possibly damaging |
0.77 |
Lilliputian
|
UTSW |
1 |
158544560 |
missense |
probably damaging |
1.00 |
Lilliputian2
|
UTSW |
1 |
158662488 |
nonsense |
probably null |
|
lilliputian3
|
UTSW |
1 |
158609973 |
splice site |
probably null |
|
Pitzel
|
UTSW |
1 |
158784215 |
missense |
probably damaging |
1.00 |
shrink
|
UTSW |
1 |
158590762 |
missense |
probably damaging |
1.00 |
R0106:Pappa2
|
UTSW |
1 |
158542547 |
missense |
probably damaging |
1.00 |
R0106:Pappa2
|
UTSW |
1 |
158542547 |
missense |
probably damaging |
1.00 |
R0172:Pappa2
|
UTSW |
1 |
158682419 |
critical splice donor site |
probably null |
|
R0194:Pappa2
|
UTSW |
1 |
158592671 |
splice site |
probably benign |
|
R0418:Pappa2
|
UTSW |
1 |
158544560 |
missense |
probably damaging |
1.00 |
R0421:Pappa2
|
UTSW |
1 |
158675650 |
missense |
probably damaging |
1.00 |
R0441:Pappa2
|
UTSW |
1 |
158590628 |
unclassified |
probably benign |
|
R0602:Pappa2
|
UTSW |
1 |
158590625 |
unclassified |
probably benign |
|
R0630:Pappa2
|
UTSW |
1 |
158660343 |
missense |
probably benign |
|
R0760:Pappa2
|
UTSW |
1 |
158544531 |
critical splice donor site |
probably null |
|
R1146:Pappa2
|
UTSW |
1 |
158682552 |
missense |
probably damaging |
1.00 |
R1146:Pappa2
|
UTSW |
1 |
158682552 |
missense |
probably damaging |
1.00 |
R1243:Pappa2
|
UTSW |
1 |
158672670 |
missense |
probably damaging |
1.00 |
R1413:Pappa2
|
UTSW |
1 |
158764124 |
missense |
probably benign |
0.00 |
R1502:Pappa2
|
UTSW |
1 |
158784858 |
missense |
probably damaging |
1.00 |
R1599:Pappa2
|
UTSW |
1 |
158684742 |
missense |
probably damaging |
1.00 |
R1689:Pappa2
|
UTSW |
1 |
158784968 |
missense |
probably damaging |
1.00 |
R1750:Pappa2
|
UTSW |
1 |
158590720 |
nonsense |
probably null |
|
R1772:Pappa2
|
UTSW |
1 |
158641938 |
missense |
possibly damaging |
0.92 |
R1832:Pappa2
|
UTSW |
1 |
158684886 |
missense |
probably damaging |
1.00 |
R1905:Pappa2
|
UTSW |
1 |
158631073 |
splice site |
probably null |
|
R1914:Pappa2
|
UTSW |
1 |
158578133 |
missense |
probably damaging |
0.97 |
R2013:Pappa2
|
UTSW |
1 |
158662498 |
missense |
probably damaging |
1.00 |
R2037:Pappa2
|
UTSW |
1 |
158784214 |
nonsense |
probably null |
|
R2118:Pappa2
|
UTSW |
1 |
158684836 |
missense |
probably damaging |
1.00 |
R2268:Pappa2
|
UTSW |
1 |
158684841 |
missense |
probably damaging |
1.00 |
R2269:Pappa2
|
UTSW |
1 |
158684841 |
missense |
probably damaging |
1.00 |
R2347:Pappa2
|
UTSW |
1 |
158592613 |
missense |
probably damaging |
1.00 |
R3024:Pappa2
|
UTSW |
1 |
158763795 |
missense |
probably benign |
0.00 |
R3706:Pappa2
|
UTSW |
1 |
158662488 |
nonsense |
probably null |
|
R3707:Pappa2
|
UTSW |
1 |
158662488 |
nonsense |
probably null |
|
R3708:Pappa2
|
UTSW |
1 |
158662488 |
nonsense |
probably null |
|
R4600:Pappa2
|
UTSW |
1 |
158642015 |
missense |
probably damaging |
1.00 |
R4737:Pappa2
|
UTSW |
1 |
158784582 |
missense |
probably benign |
|
R4738:Pappa2
|
UTSW |
1 |
158784582 |
missense |
probably benign |
|
R4739:Pappa2
|
UTSW |
1 |
158784572 |
missense |
probably damaging |
0.99 |
R4739:Pappa2
|
UTSW |
1 |
158784582 |
missense |
probably benign |
|
R4788:Pappa2
|
UTSW |
1 |
158611487 |
missense |
possibly damaging |
0.86 |
R4798:Pappa2
|
UTSW |
1 |
158684949 |
missense |
probably damaging |
0.99 |
R4952:Pappa2
|
UTSW |
1 |
158684706 |
missense |
probably null |
1.00 |
R5121:Pappa2
|
UTSW |
1 |
158666197 |
missense |
probably benign |
0.01 |
R5144:Pappa2
|
UTSW |
1 |
158784703 |
missense |
probably benign |
0.03 |
R5159:Pappa2
|
UTSW |
1 |
158589189 |
missense |
probably damaging |
1.00 |
R5278:Pappa2
|
UTSW |
1 |
158609973 |
splice site |
probably null |
|
R5428:Pappa2
|
UTSW |
1 |
158642355 |
missense |
possibly damaging |
0.53 |
R5452:Pappa2
|
UTSW |
1 |
158666172 |
missense |
probably benign |
0.00 |
R5477:Pappa2
|
UTSW |
1 |
158784308 |
missense |
probably benign |
0.00 |
R5504:Pappa2
|
UTSW |
1 |
158675615 |
missense |
probably benign |
0.00 |
R5852:Pappa2
|
UTSW |
1 |
158544584 |
missense |
probably damaging |
1.00 |
R6003:Pappa2
|
UTSW |
1 |
158763820 |
missense |
probably benign |
0.23 |
R6129:Pappa2
|
UTSW |
1 |
158542567 |
nonsense |
probably null |
|
R6137:Pappa2
|
UTSW |
1 |
158699113 |
missense |
probably damaging |
1.00 |
R6374:Pappa2
|
UTSW |
1 |
158784215 |
missense |
probably damaging |
1.00 |
R6472:Pappa2
|
UTSW |
1 |
158662369 |
missense |
probably damaging |
1.00 |
R6804:Pappa2
|
UTSW |
1 |
158764438 |
missense |
probably benign |
0.24 |
R7020:Pappa2
|
UTSW |
1 |
158675579 |
missense |
probably damaging |
0.98 |
R7051:Pappa2
|
UTSW |
1 |
158784753 |
missense |
unknown |
|
R7082:Pappa2
|
UTSW |
1 |
158590689 |
missense |
possibly damaging |
0.65 |
R7111:Pappa2
|
UTSW |
1 |
158784096 |
missense |
probably benign |
0.38 |
R7213:Pappa2
|
UTSW |
1 |
158764456 |
missense |
possibly damaging |
0.93 |
R7575:Pappa2
|
UTSW |
1 |
158642100 |
missense |
probably damaging |
1.00 |
R7587:Pappa2
|
UTSW |
1 |
158678701 |
missense |
probably damaging |
1.00 |
R7826:Pappa2
|
UTSW |
1 |
158764010 |
nonsense |
probably null |
|
R7957:Pappa2
|
UTSW |
1 |
158589131 |
nonsense |
probably null |
|
R8007:Pappa2
|
UTSW |
1 |
158609874 |
missense |
probably damaging |
0.99 |
R8050:Pappa2
|
UTSW |
1 |
158675970 |
missense |
probably damaging |
1.00 |
R8063:Pappa2
|
UTSW |
1 |
158764126 |
missense |
possibly damaging |
0.79 |
R8068:Pappa2
|
UTSW |
1 |
158763555 |
missense |
possibly damaging |
0.87 |
R8128:Pappa2
|
UTSW |
1 |
158764234 |
missense |
possibly damaging |
0.75 |
R8264:Pappa2
|
UTSW |
1 |
158682543 |
missense |
probably damaging |
1.00 |
R8317:Pappa2
|
UTSW |
1 |
158592530 |
missense |
probably damaging |
1.00 |
R8499:Pappa2
|
UTSW |
1 |
158764092 |
missense |
probably damaging |
1.00 |
R8744:Pappa2
|
UTSW |
1 |
158611487 |
missense |
possibly damaging |
0.86 |
R8793:Pappa2
|
UTSW |
1 |
158678731 |
missense |
probably damaging |
1.00 |
R8932:Pappa2
|
UTSW |
1 |
158590762 |
missense |
probably damaging |
1.00 |
R9004:Pappa2
|
UTSW |
1 |
158764518 |
missense |
possibly damaging |
0.67 |
R9004:Pappa2
|
UTSW |
1 |
158763979 |
missense |
probably damaging |
1.00 |
R9088:Pappa2
|
UTSW |
1 |
158763927 |
missense |
probably damaging |
1.00 |
R9191:Pappa2
|
UTSW |
1 |
158684988 |
missense |
probably damaging |
1.00 |
R9243:Pappa2
|
UTSW |
1 |
158763763 |
missense |
probably damaging |
0.99 |
R9280:Pappa2
|
UTSW |
1 |
158675533 |
missense |
possibly damaging |
0.77 |
R9301:Pappa2
|
UTSW |
1 |
158672614 |
missense |
probably damaging |
0.96 |
R9306:Pappa2
|
UTSW |
1 |
158764492 |
missense |
probably damaging |
1.00 |
R9367:Pappa2
|
UTSW |
1 |
158784542 |
missense |
probably benign |
0.40 |
R9471:Pappa2
|
UTSW |
1 |
158642029 |
missense |
probably benign |
0.04 |
R9544:Pappa2
|
UTSW |
1 |
158784817 |
missense |
probably damaging |
0.99 |
R9680:Pappa2
|
UTSW |
1 |
158609818 |
missense |
possibly damaging |
0.78 |
R9762:Pappa2
|
UTSW |
1 |
158684948 |
missense |
probably damaging |
1.00 |
R9774:Pappa2
|
UTSW |
1 |
158675920 |
missense |
probably damaging |
0.99 |
R9776:Pappa2
|
UTSW |
1 |
158611481 |
missense |
probably damaging |
1.00 |
X0058:Pappa2
|
UTSW |
1 |
158641967 |
missense |
probably null |
|
X0061:Pappa2
|
UTSW |
1 |
158764188 |
missense |
possibly damaging |
0.87 |
Z1176:Pappa2
|
UTSW |
1 |
158784503 |
missense |
probably benign |
|
Z1176:Pappa2
|
UTSW |
1 |
158642386 |
missense |
probably damaging |
1.00 |
Z1176:Pappa2
|
UTSW |
1 |
158642384 |
missense |
probably damaging |
1.00 |
|
Mode of Inheritance |
Unknown |
Local Stock | |
Repository | |
Last Updated |
2019-09-04 9:30 PM
by Anne Murray
|
Record Created |
2019-01-22 2:13 PM
by Bruce Beutler
|
Record Posted |
2019-01-30 |
Phenotypic Description |
The Gulliver phenotype was identified among G3 mice of the pedigree R4952, some of which showed reduced body weights compared to wild-type littermates (Figure 1). Some mice also showed reduced frequencies of CD44+ CD8 T cells in the peripheral blood (Figure 2).
|
Nature of Mutation |
Whole exome HiSeq sequencing of the G1 grandsire identified 85 mutations. Both of the above phenotypes were linked to mutations in two genes on chromosome 1: Pappa2 and Gm4846. The mutation in Pappa2 was presumed causative as the body weight phenotype in gulliver mimics that of other alleles of Pappa2. The Pappa2 mutation is a C to T transition at base pair 158,857,136 (v38) on chromosome 1, or base pair 123,392 in the GenBank genomic region NC_000067. The strongest association was found with an additive model of inheritance, wherein one variant homozygote and 16 heterozygous mice departed phenotypically from seven homozygous reference mice with a P value of 4.259 x 10-6 (Figure 3). The mutation corresponds to residue 2,432 in the mRNA sequence NM_001085376 within exon 4 of 22 total exons.
2416 AACTACATGAGCTACACAGATGATGAGTGCACT
806 -N--Y--M--S--Y--T--D--D--E--C--T-
|
The mutated nucleotide is indicated in red. The mutation results in a threonine to isoleucine substitution at position 811 (T811I) in the PAPP-A2 protein, and is strongly predicted by Polyphen-2 to cause loss of function (score = 1.000).
|
Illustration of Mutations in
Gene & Protein |
|
---|
Protein Prediction |
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 4) (1). The mutation results in a threonine to isoleucine substitution at position 811 (T811I); Thr811 is within the peptidase domain. Please see the record Lilliputian for more information about Pappa2.
|
Putative Mechanism | 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 Gulliver mice indicates loss of PAPP-A2-associated function.
|
Primers |
PCR Primer
Gulliver_pcr_F: TTTCACTTTCAAGCTCTCATGGAAG
Gulliver_pcr_R: AGAATCCTGTGATGATCCCTGTAG
Sequencing Primer
Gulliver_seq_F: TTCAAGCTCTCATGGAAGAGAATCC
Gulliver_seq_R: CCTGTGATGATCCCTGTAGAGAGAC
|
Genotyping | PCR program 1) 94°C 2:00 2) 94°C 0:30 3) 55°C 0:30 4) 72°C 1:00 5) repeat steps (2-4) 40x 6) 72°C 10:00 7) 4°C hold
The following sequence of 400 nucleotides is amplified (chromosome 1, - strand):
1 agaatcctgt gatgatccct gtagagagac agtgccatcc atggagacag gagacctgtg 61 tgctgacact gctcccacac ccaagagcaa gctgtgtcgg gacccagagc cagctaatga 121 cacctgtggc ttcaccctct tcccaggggc tccgttcaat aactacatga gctacacagg 181 tatcaccaca agcccaatgt ttttgtttca ttaagatcat ttagtgtctt tgggaattgg 241 taggctgtag ctaatggagc caggaagatt catgtcacat gaatactttg tgttgggtat 301 tcctgtattt tccgtgtgtt tgtttgaagt ttgacaaaat attgagatag taaatggtct 361 tgttgattgg attctcttcc atgagagctt gaaagtgaaa
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red. |
References | 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.
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.
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.
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Science Writers | Anne Murray |
Illustrators | Diantha La Vine |
Authors | Zhao Zhang, Xue Zhong, Jin Huk Choi, and Bruce Beutler |