MUTATIONS IN PEX10 IS THE CAUSE OF ZELLWEGER PEROXISOME DEFICIENCY SYNDROME OF COMPLEMENTATION GROUP-B

Peroxisome biogenesis disorders (PBD), such as Zellweger syndrome, are autosomal recessive diseases caused by a deficiency in peroxisome ass embly as well as a malfunction of the peroxisomes, where at least 10 g enotypes have been reported. We have isolated a human PEX10 cDNA (HsPE X10) by an expressed sequence tag homology search on a human DNA datab ase using yeast PEX10 from Hansenula polymorpha, followed by screening of a human liver cDNA library. This cDNA encodes a peroxisomal protei n (a peroxin Pex10p) comprising 326 amino acids, with two putative tra nsmembrane segments and a C3HC4 zinc finger RING motif, Both the N- an d C-terminal regions of Pex10p are exposed to the cytosol, as assessed by an expression study of epitope-tagged Pex10p. HsPEX10 expression m orphologically and biochemically restored peroxisome biogenesis in fib roblasts from Zellweger patients of complementation group B in Japan ( complementation group VII in the USA). One patient (PBDB-01) possessed a homozygous, inactivating mutation, a 2 bp deletion immediately upst ream of the RING motif, which resulted in a frameshift,;altering 65 am ino acids from the normal. This implies that the C-terminal part, incl uding the RING finger, is required for biological function of Pex10p, PEX10 cDNA derived from patient PBDB-01 was defective in peroxisome-re storing activity when expressed in patient fibroblasts, These results demonstrate that mutation in PEX10 is the genetic cause of complementa tion group B PBD.