Rhizomelic chondrodysplasia punctata, type 1 (RCDP1) is an autosomal recessive disorder that is a member of a family of disorders that result from defects in the biogenesis and/or functioning of the peroxisomes and are referred to as peroxisome biogenesis disorders, PBDs. The term "chondrodyplasia punctata" refers to the stippled foci of calcifications in the cartilage. Rhizomelia refers to the hip and shoulder joints and is reflected by a disproportion in the length of the proximal limb.
The PBDs are divided into two clinical spectra which includes RCDP and the Zellweger spectrum PBDs. The Zellweger spectrum PBDs includes Zellweger syndrome, infantile Refsum disease (IRD), and neonatal adrenoleukodystrophy (NALD). Zellweger syndrome represents the extreme of the clinical manifestation of PBDs with patients rarely surviving their first year of life. Zellweger syndrome is associated with either severe, moderate or mild defects in all peroxisome functions. RCDP1 is distinguished from the Zellweger spectrum PBDs by manifesting with more severe skeletal involvement as well as specific biochemical characteristics as described below.
RCDP1 results from mutations in the PEX7 gene that is involved in peroxisome biogenesis (PEX genes encoding proteins termed peroxins). The PEX7 gene is located on chromosome 6q22–q24 spanning 102 kb and composed of 10 exons. As discussed below, the PEX7 encoded protein is the receptor for proteins containing a type-2 peroxisomal targeting sequence, PTS2.
There are three additional disorders with clinical features of RCDP1 called rhizomelic chondrodysplasia type 2 (RCDP2), type 3 (RCDP3), and type 5 (RCDP5). Although the morphological characteristic of the RCDP disorders are similar, only RCDP1 and RCDP5 are classified as peroxisomal biogenesis disorders. RCDP5 results from defects in the PEX5 gene (also known as the peroxisome receptor 1, PXR1 gene). As described in the next paragraph, the PEX5 protein recognizes proteins with PTS1 sequences. RCDP2 and RCDP3 are referred to as single peroxisomal enzyme disorders. RCDP2 results from defects in the gene encoding dihydroxyacetone phosphate acyltransferase (DHAPAT). The DHAPAT gene (symbol: GNPAT for glyceronephosphate O-acyltransferase) is found on chromosome 1q42 and is composed of 17 exons that encode a 680 amino acid protein which contains a PTS1 motif. DHAPAT is a peroxisomal enzyme carrying out one of two pathways in the synthesis of phosphatidic acid (see the Lipid Synthesis page) whose product can be diverted to the ether lipid (the plasmalogens) biosynthesis pathway which occurs in peroxisomes. RCDP3 results from defects in the gene encoding alkyldihydroxyacetone phosphate acyltransferase (alkyl-DHAP synthase). The alkyl-DHAP synthase gene (symbol: AGPS for alkylglycerone phosphate synthase) is located on chromosome 2q31 and encodes a 658 amino acid protein which contains a PTS2 motif. Alkyl-DHAP synthase introduces the ether linkage in plasmalogens.
The peroxisomes are a single membrane organelle, similar to lysosomes, present in virtually all eukaryotic cells. The peroxisome is a specialized enzyme "factory" that contains in excess of 50 different enzymes involved in a variety of metabolic processes including β-oxidation of very long chain fatty acids, α-oxidation of fatty acids and synthesis of ether-lipids. Proteins that are involved in and necessary for correct peroxisome biogenesis are called peroxins (PEX). At least 15 PEX genes have been identified in humans. Enzymes that are targeted to the peroxisomes contain either of two amino acid consensus elements called peroxisome targeting sequences (PTS). The PTS1 is a C-terminal consensus sequence of –(S/A/C)(K/R/H)(L/M) referred to as the SKL motif. This sequence element is recognized by a cytosolic PTS1 receptor encoded by the PEX5 gene. There are two isoforms of PEX5 encoded proteins in humans identified as Pex5pS and Pex5pL (for short and long forms, respectively). The Pex5pL protein has an internal 37 amino acid insertion, hence the "long" designation. The PTS2 is an N-terminal consensus sequence of –(R/K)(L/V/I/Q)XX(L/V/I/H/Q)(L/S/G/A/K)X(H/Q)(L/A/F)–, (where X represents any amino acid). The PTS2 receptor is encoded by the PEX7 gene and the encoded protein is referred to as Pex7p. Proteins that are targeted to the membrane of the peroxisome (called peroxisome membrane proteins, PMPs) contain a consensus sequence identified as the PEX19 binding site (PEX19BS) and this site is recognized by the membrane protein receptor encoded by the PEX19 gene.
Pex5pS, Pex5L, and Pex7p interact with newly synthesized target proteins in the cytosol and direct them to the peroxisome. On the membrane of the peroxisome is a component of the protein import machinery encoded by the PEX14 gene called Pex14p. Following interaction of Pex5pS or Pex5pL, bound to a protein containing a PTS1 sequence, with Pex14p, the PTS1 containing protein is transferred into the peroxisome. The activity of Pex7p in peroxisome protein import actually requires Pex5pL as well. PTS2 containing proteins interact with Pex7p and then, in conjunction with Pex5pL, the complex interacts with Pex14p and the PTS2 containing protein is transferred into the peroxisome. Very few proteins contain a PTS2 sequence but one enzyme of note is phytanoyl-CoA hydroxylase (PHYH) which is defective in classic Refsum disease.
As the name of the syndrome implies, RCDP1 patients have a striking shortening of their proximal limbs which is due to a severe disruption in endochondral bone formation. RCDP is a rare, multisystem, developmental disorder characterized by the presence of stippled foci in the epiphyses especially in the knees, hips, shoulders and elbows. Additional dysmorphic alterations include coronal vertebral clefting, flat nasal bridge, frontal bossing, dwarfing, and joint contractures. Cataracts are present in about 75% of cases, and skin changes in about 30%. Biochemically, RCDP patients have subnormal levels of red cell plasmalogens and progressive accumulation of phytanic acid starting from normal at birth and increasing to levels more than 10 times normal by age 1 year. There are several disorders that are associated with punctate cartilaginous changes such as in some forms of Zellweger syndrome. Thus, care must be taken when attempting a definitive diagnosis of RCDP. The association of punctate calcifications with rhizomelia, red blood cells deficient in plasmalogens, and accumulation of phytanic acid would be a strong indication of RCDP. RCDP patients have severe psychomotor retardation and most do not survive beyond two years of age.