Molecular Characteristics
Prolyl 4-hydroxylases (P4Hs) are enzymes that hydroxylize proline residues to 4-hydroxyproline. There are two common types of P4Hs, one that exists in the endoplasmic reticulum (ER) and acts on the X-Pro-Gly sequence in pro-collagen chains to increase its stability, and another that exists in the nucleus and cytosol and acts on hypoxia-inducible factor (HIF) to mark it for degradation. P4HTM encodes an atypical P4H that localizes to the ER membrane and acts on HIF. It appears to play a role in HIF-mediated erythropoietin production, in addition to important roles in the retina and basement membrane of kidneys (based on zebrafish and mouse studies).
Mutations and pathophysiology
P4HTM is located at 3p21.31. A few selected examples of pathogenic variants reported by Maddirevula et al. in four different families with HIDEA syndrome are described below:
c.888-3C>A (p.Arg296_Arg358delinsSer) in family 1
c.1410_1411delinsAA (p.Arg471Ser) in family 2
c.949delG (p.Val317Phefs*30) in family 3
c.819dupG (p.Asn274Glufs*11) in family 4
These variants were predicted to lead a decrease in P4HTM activity.
P4HTM