Human-Specific Abnormal Alternative Splicing of Wild-Type Induces Premature Termination of Polycystin-1.

Background: The major form of autosomal dominant polycystic kidney disease is caused by heterozygous mutations in , the gene that encodes polycystin-1 (PC1). Unlike genes in the mouse and most other mammals, human is unusual in that it contains two long polypyrimidine tracts in introns 21 and 22 (2.5 kbp and 602 bp, respectively; 97% cytosine and thymine).

Do ASARM peptides play a role in nephrogenic systemic fibrosis?

Nephrogenic systemic fibrosis (NSF) is a devastating condition associated with gadolinium (Gd3+)-based contrast agents (GBCAs) in patients with kidney disease. The release of toxic Gd3+ from GBCAs likely plays a major role in NSF pathophysiology. The cause and etiology of Gd3+ release from GBCAs is unknown.

Age dependent regulation of bone-mass and renal function by the MEPE ASARM-motif.

Context: Mice with null mutations in matrix extracellular phosphoglycoprotein (MEPE) have increased bone mass, increased trabecular density and abnormal cancellous bone (MN-mice). These defects worsen with age and MEPE overexpression induces opposite effects. Also, genome wide association studies show that MEPE plays a major role in bone mass.

SPR4-peptide alters bone metabolism of normal and HYP mice.

Context: ASARM-peptides are substrates and ligands for PHEX, the gene responsible for X-linked hypophosphatemic rickets (HYP). PHEX binds to the DMP1-ASARM-motif to form a trimeric-complex with α5β3-integrin on the osteocyte surface and this suppresses FGF23 expression. ASARM-peptide disruption of this complex increases FGF23 expression.

PHEX mimetic (SPR4-peptide) corrects and improves HYP and wild type mice energy-metabolism.

Context: PHEX or DMP1 mutations cause hypophosphatemic-rickets and altered energy metabolism. PHEX binds to DMP1-ASARM-motif to form a complex with α5β3 integrin that suppresses FGF23 expression. ASARM-peptides increase FGF23 by disrupting the PHEX-DMP1-Integrin complex.