Rhizomelic chondrodysplasia punctata is a peroxisomal protein targeting disease caused by a non-functional PTS2 receptor

Abstract

Rhizomelic chondrodysplasia punctata (RCDP) is an autosomal recessive disease characterized clinically by a disproportionately short stature primarily affecting the proximal parts of the extremities, typical dysmorphic facial appearance, congenital contractures and severe growth and mental retardation. Although some patients have single enzyme deficiencies, the majority of RCDP patients (86%) belong to a single complementation group (CG11, also known as complementation group I, Amsterdam nomenclature). Cells from CG11 show a tetrad of biochemical abnormalities: a deficiency of i) dihydroxyacetonephosphate acyltransferase, ii) alkyldihydroxyacetonephosphate synthase, iii) phytanic acid alpha-oxidation and iv) inability to import peroxisomal thiolase. These deficiencies indicate involvement of a component required for correct targeting of these peroxisomal proteins. Deficiencies in peroxisomal targeting are also found in Saccharomyces cerevisiae pex5 and pex7 mutants, which show differential protein import deficiencies corresponding to two peroxisomal targeting sequences (PTS1 and PTS2). These mutants lack their PTS1 and PTS2 receptors, respectively. Like S. cerevisiae pex cells, RCDP cells from CG11 cannot import a PTS2 reporter protein. Here we report the cloning of PEX7 encoding the human PTS2 receptor, based on its similarity to two yeast orthologues. All RCDP patients from CG11 with detectable PEX7 mRNA were found to contain mutations in PEX7. A mutation resulting in C-terminal truncation of PEX7 cosegregates with the disease and expression of PEX7 in RCDP fibroblasts from CG11 rescues the PTS2 protein import deficiency. These findings prove that mutations in PEX7 cause RCDP, CG11.

Getting a camel through the eye of a needle: the import of folded proteins by peroxisomes

“…The more pronounced the structural effect of a mutation on PEX5, the more severe the Zellweger spectrum phenotype observed (Braverman et al, 1998;Weller et al, 2003;Maynard and Berg, 2007;Ebberink et al, 2009). Mutants of PEX7 which result in truncated proteins being formed cause a PTS2 import deficiency, which is symptomatic of patients with the condition rhizomelic chondrodysplasia punctata (Table 1) (Motley et al, 1997;Purdue et al, 1997).…”

Molecular basis of rhizomelic chondrodysplasia punctata type I: High frequency of the Leu‐292 Stop mutation in 38 patients

“…We now report on the frequency of the Leu-292 Stop mutation which was earlier identiÐed in some patients et al et al In a series of (Braverman 1997 ;Motley 1997). 38 patients we found a very high frequency of the Leu-292 Stop mutation with important implications for carrier-detection and prenatal diagnosis.…”

“…Previous studies by Braverman et al 1997 and ourselves et al have led (Motley 1997) to the identiÐcation of the Leu-292 Stop mutation leading to a truncated protein with no biological activity. We have now studied the occurrence of the Leu-292 Stop mutation in a series of 38 patients.…”

“…for the correct expression of all four enzymes. The gene involved, PEX7, was recently identiÐed simultaneously by three groups of investigators including our own et al et al et al It encodes the per- (Braverman 1997 ;Motley 1997 ;Purdue 1997). oxisomal PTS2 receptor which is involved in the recognition of peroxisomal proteins containing a certain peroxisome targeting signal (PTS2) in the cytosol and their subsequent delivery to the peroxisome and Subramani (Rachubinski 1995).…”

Peroxisomes: simple in function but complex in maintenance

“…In 11 cases, the molecular basis for a peroxisomal disease could be related to a nonfunctional Pex protein. Rhizomelic chondrodysplasia punctata (pex7) and the cerebrohepatorenal syndrome of Zellweger (pex5) are typical examples of a new and surprising class of diseases that are caused by defects in protein trafficking [40][41][42][43] . Although these new insights provide no prospect for therapy, they open up the option of prenatal diagnosis.…”