A MEMBER OF A FAMILY OF SULFATE-ACTIVATING ENZYMES CAUSES MURINE BRACHYMORPHISM

Sulfation is critical to the function of a wide variety of biomolecule s. This common modification requires the enzymatic synthesis of an act ivated sulfate donor, phosphoadenosine-phosphosulfate (PAPS), In highe r organisms PAPS synthesis is catalyzed by a bifunctional sulfurylase kinase (SK) polypeptide having both ATP-sulfurylase and adenosine-phos phosulfate kinase activities, We report the identification of a gene f amily encoding murine SK proteins with these two activities. A family member, SK2, colocalizes with the locus for the autosomal recessive mu rine phenotype brachymorphism. Brachymorphic mice have normal lifespan s, but abnormal hepatic detoxification, bleeding times, and postnatal growth, the latter being attributed to under-sulfation of cartilage pr oteoglycan, A missense mutation in the SK2 coding sequence of bm mice that alters a highly conserved amino acid residue destroys adenosine-p hosphosulfate kinase activity and therefore the ability of SK2 to synt hesize PAPS, We conclude that a family of SK genes are responsible for sulfate activation in mammals, that a mutation in SK2 causes murine b rachymorphism, and that members of this gene family have nonredundant, tissue-specific roles.