Phenotypic Mutation 'Lilliputian2' (pdf version)
Allele | Lilliputian2 |
Mutation Type |
nonsense
|
Chromosome | 1 |
Coordinate | 158,662,488 bp (GRCm39) |
Base Change | A ⇒ T (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 |
Tyrosine changed to Stop codon
|
Institutional Source | Beutler Lab |
Gene Model |
predicted gene model for protein(s):
[ENSMUSP00000124022]
|
AlphaFold |
E9PZ87 |
SMART Domains |
Protein: ENSMUSP00000124022 Gene: ENSMUSG00000073530 AA Change: Y1162*
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
|
Meta Mutation Damage Score |
0.9716 |
Is this an essential gene? |
Non Essential (E-score: 0.000) |
Phenotypic Category |
Autosomal Semidominant |
Candidate Explorer Status |
loading ... |
Single pedigree Linkage Analysis Data
|
|
Penetrance | |
Alleles Listed at MGI | All Mutations and Alleles(6) : 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 |
Gulliver
|
UTSW |
1 |
158684706 |
missense |
probably null |
1.00 |
Lilliputian
|
UTSW |
1 |
158544560 |
missense |
probably damaging |
1.00 |
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 |
Autosomal Semidominant |
Local Stock | |
Repository | |
Last Updated |
2019-09-04 9:44 PM
by Diantha La Vine
|
Record Created |
2016-01-25 10:58 AM
|
Record Posted |
2016-06-02 |
Phenotypic Description |
The Lilliputian2 phenotype was identified among G3 mice of the pedigree R3707, 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 41 mutations. The body weight phenotype was linked to mutations in two genes on chromosome 1: Pappa2 and Pigc. The mutation in Pappa2 was presumed to be causative because the Lilliputian phenotype mimics that of other Pappa2 mouse models (see MGI). The mutation in Pappa2 is a T to A transversion at base pair 158,834,918 (v38) on chromosome 1, or base pair 145,606 in the GenBank genomic region NC_000067 encoding Pappa2. Linkage was found with an additive model of inheritance (P = 4.70 x 10-4), wherein five variant homozygotes and seven heterozygotes departed phenotypically from 11 homozygous reference mice (Figure 2). The mutation corresponds to residue 3,486 in the mRNA sequence NM_001085376 in exon 10 of 22 total exons.
3469 AGCCTTTGCTACAGGTATGAGGGAGATGGGGTT
1157 -S--L--C--Y--R--Y--E--G--D--G--V-
|
The mutated nucleotide is indicated in red. The mutation results in substitution of tyrosine 1,162 to a premature stop codon (Y1162*) in the PAPP-A2 protein.
|
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 3) (1). The mutation in Lilliputian2 results in substitution of tyrosine 1,162 to a premature stop codon (Y1162*). Amino acid 1,162 is within an undefined domain between the FN3 domain and the first CCP 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 Lilliputian2 mice indicates loss-of-function of PAPP-A2Lilliputian2.
|
Primers |
PCR Primer
Lilliputian2_pcr_F: AGCCATGACTCCATTCTTCTGG
Lilliputian2_pcr_R: TGCTTCTTCCCTCATAAAGAGTG
Sequencing Primer
Lilliputian2_seq_F: CTGGCTTAACTTACCATTGAATGAGG
Lilliputian2_seq_R: TCTTCCCTCATAAAGAGTGAAAAAC
|
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 422 nucleotides is amplified (chromosome 1, - strand):
1 tgcttcttcc ctcataaaga gtgaaaaacc cctcctctcc aacagtgttg gggttggagt 61 tttggctggt actgcactct tcaattatca caagattgtc tttagagagt tgaagaattg 121 ctgggaatac tctcatttta aatttcccct aaaagatatg aaaaaaaagt cctaaatgct 181 atccatgttt ttgcagggga gccaagcctt tgctacaggt atgagggaga tggggtttgt 241 gaagattttg agaaggaaag catcatcaca gactgtggcc tccacactcc tgaaggatat 301 ttggatcagt gggctagcca ggcttattcc taccatgaag acaaggagaa atgtcctgtt 361 tccctggtaa caggagaacc tcattcaatg gtaagttaag ccagaagaat ggagtcatgg 421 ct
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 | Peter Jurek |
Authors | Emre Turer and Bruce Beutler |