FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a secreted metalloproteinase which cleaves insulin-like growth factor binding proteins (IGFBPs). It is thought to be involved in local proliferative processes such as wound healing and bone remodeling. Low plasma level of this protein has been suggested as a biochemical marker for pregnancies with aneuploid fetuses. [provided by RefSeq, Jul 2008] PHENOTYPE: Homozygous null mutants are smaller than normal with delayed ossification, but are otherwise normal and fertile. [provided by MGI curators]
Figure 1.Untersuchen mice exhibit reduced body weights compared to wild-type littermates. Scaled weights are shown. Abbreviations: WT, wild-type; REF, homozygous reference mice; HET, heterozygous variant mice; VAR, homozygous variant mice. Mean (μ) and standard deviation (σ) are indicated.
The untersuchen phenotype was identified among G3 mice of the pedigree R2127, some of which showed reduced body weights compared to wild-type littermates (Figure 1).
Nature of Mutation
Figure 2.Linkage mapping of the reduced body weight phenotype using a recessive model of inheritance. Manhattan plot shows -log10 P values (Y-axis) plotted against the chromosome positions of 94 mutations (X-axis) identified in the G1 male of pedigree R2127. Weight data are shown for single locus linkage analysis without consideration of G2 dam identity. Horizontal pink and red lines represent thresholds of P = 0.05, and the threshold for P = 0.05 after applying Bonferroni correction, respectively.
Whole exome HiSeq sequencing of the G1 grandsire identified 94 mutations. The body weight phenotype was linked to mutations in several genes. However, the mutation in Pappa was presumed causative as the body weight phenotype in the untersuchen mice mimics that of mice expressing other mutant Pappa alleles (see MGI). The mutation in Pappa is a T to A transversion at base pair 65,297,257 (v38) on chromosome 4, or base pair 173,084 in the GenBank genomic region NC_000070. Linkage was found with a recessive model of inheritance, wherein one variant homozygote departed phenotypically from 11 homozygous reference mice and 12 heterozygous mice with a P value of 0.000366 (Figure 2).
The mutation corresponds to residue 3,768 in the mRNA sequence NM_021362 within exon 13 of 22 total exons.
The mutated nucleotide is indicated in red. The mutation results in a leucine to methionine substitution at position 1,134 (L1134M) in the PAPP-A protein, and is strongly predicted by Polyphen-2 to be damaging (score = 1.000).
Figure 3. Domain organization of PAPP-A. The untersuchen mutation results in a leucine to methionine substitution at position 1134. This image is interactive. Other mutations found in PAPP-A are noted in red. Click on each allele for more information. Abbreviations: SP, signal peptide; LNR: Lin12/Notch repeats; CCP, complement control protein
Pappa encodes pregnancy-associated plasma protein A (PAPP-A; alternatively, IGFBP4 protease or differentially expressed in placenta 1 [DIPLA1]), a member of the pappalysin subfamily of the metzincin protease family along with PAPP-A2 (see the record for Lilliputian) and ulilysin. PAPP-A is initially translated as a 1,624 proprotein; cleavage of the signal peptide and the propeptide (amino acids 23-80) generates the mature 1,544 amino acid peptide (1). PAPP-A has several domains, including a signaling peptide (amino acids 1-22), a laminin G-like domain, three Lin12/Notch repeats (LNRs), a metalloprotease region (amino acids 272-583), and five complement control protein (CCP) domains (alternatively, short consensus repeat [SCR] or Sushi domains; amino acids 1210-1279, 1280-1341, 1342-1409, 1410-1470, and 1473-1553) (Figure 3) (2).
The untersuchen mutation results in a leucine to methionine substitution at position 1,134 (L1134M); Leu1134 is within an undefined region before the first CCP domain.
Please see the record caer for more information about Pappa.
PAPP-A is a secreted metalloproteinase that cleaves insulin-like growth factor binding protein 2 (IGFBP2), IGFBP4, and IGFBP5. The IGFBPs regulate 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. IGFBPs are carrier proteins that regulate the bioavailability of insulin-like growth factors (IGFs) by prolonging their-half-life and circulation turnover. IGFs are essential for the regulation of growth and development by influencing the proliferation, differentiation, and apoptosis of osteoblasts (3;4). IGFs bind to two types of receptors, IGF-IR and IGF-IIR, subsequently activating downstream tyrosine kinase pathways. In IGF-I-associated signaling, both the IRS-1/phosphoinositide 3-kinase/serine–threonine kinase pathway and the Ras/mitogen-activated protein kinase/extracellular signal-regulated kinase pathway are activated, which subsequently promote cell proliferation, tissue differentiation, and protection from apoptosis.
Pappa-deficient (Pappa-/-) mice showed reduced body sizes and weights (60 to 70% of wild-type mice) as well as delayed bone ossification (5). The phenotype of the untersuchen mice mimics that of the Pappa-/- mice, indicating loss of PAPP-A function. PAPP-A functions as a growth-promoting enzyme through its role in cleaving IGFBPs (and subsequent release of bioactive IGF). IGFBP4 cleavage is required to activate most, if not all, IGF2-mediated growth-promoting activity.