Mutations in PEX10 is the cause of Zellweger peroxisome deficiency syndrome of complementation group B |
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Authors: | Okumoto K; Itoh R; Shimozawa N; Suzuki Y; Tamura S; Kondo N; Fujiki Y |
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Institution: | Department of Biology, Faculty of Science, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan. |
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Abstract: | Peroxisome biogenesis disorders (PBD), such as Zellweger syndrome, are
autosomal recessive diseases caused by a deficiency in peroxisome assembly
as well as a malfunction of the peroxisomes, where at least 10 genotypes
have been reported. We have isolated a human PEX10 cDNA (HsPEX10) by an
expressed sequence tag homology search on a human DNA database using yeast
PEX10 from Hansenula polymorpha, followed by screening of a human liver
cDNA library. This cDNA encodes a peroxisomal protein (a peroxin Pex10p)
comprising 326 amino acids, with two putative transmembrane segments and a
C3HC4zinc finger RING motif. Both the N- and C-terminal regions of Pex10p
are exposed to the cytosol, as assessed by an expression study of
epitope-tagged Pex10p. HsPEX10 expression morphologically and biochemically
restored peroxisome biogenesis in fibroblasts 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 upstream of the RING motif, which resulted in a
frameshift, altering 65 amino acids from the normal. This implies that the
C-terminal part, including the RING finger, is required for biological
function of Pex10p. PEX10 cDNA derived from patient PBDB-01 was defective
in peroxisome-restoring activity when expressed in patient fibroblasts.
These results demonstrate that mutation in PEX10 is the genetic cause of
complementation group B PBD.
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