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

chondrodysplasia punctata (RCDP; Mckusick 215100 is an autosomal Rhizomelic recessive disease characterized by a disproportionate stature, typical facial appearance, congenital contractures, eye abnormalities and severe growth and mental retardation, although patients have been described with a much milder clinical presentation (see for instance et al Apart from the clinical heterogeneity Smeitink 1992). there is also biochemical heterogeneity, suggesting the involvement of at least three distinct genes. In most RCDP patients ([90%) there is a tetrad of biochemical abnormalities including a deÐciency of dihydroxyacetonephosphate acyltransferase (DHAPAT), alkyldihydroxyacetonephosphate synthase (alkyl DHAP synthase), phytanoyl-CoA hydroxylase, and peroxisomal thiolase I (see et al for Wanders 1996 review). A minority of patients lack this tetrad of abnormalities and su†er from an isolated deÐciency of DHAPAT or alkyl DHAP synthase deÐciency. We propose to call these three biochemical phenotypes RCDP type I, type II and type III, respectively. Genetic complementation studies have revealed that all type I RCDP patients characterized by the tetrad of biochemical abnormalities belong to a single complementation group, suggesting the involvement of a single gene et al (Heikoop Obviously, the product of this gene is of crucial importance, being required 1992). 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