Last Updated: September 15, 2022
Introduction to RCDP
Rhizomelic chondrodysplasia punctata (RCDP) represents a family of disorders resulting from mutations in genes encoding functions associated with the biogenesis of peroxisomes or the metabolic processes of the peroxisomes. 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.
Rhizomelic chondrodysplasia punctata, type 1 (RCDP1) is the most common form of RCDP. RCDP1 is an autosomal recessive disorder that is a member of a family of disorders that result from defects in the biogenesis of the peroxisomes and are referred to as peroxisome biogenesis disorders, PBD. The PBD are caused by peroxisomal assembly defects. Rhizomelic chondrodysplasia punctata, type 5 (RCDP5) is also a member of the PBD family of disorders.
The PBD are divided into two clinical spectra which includes RCDP and the Zellweger spectrum PBD. The Zellweger spectrum PBD includes Zellweger syndrome, infantile Refsum disease (IRD), and neonatal adrenoleukodystrophy (NALD). Zellweger syndrome represents the extreme of the clinical manifestation of PBD 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 PBD by manifesting with more severe skeletal involvement as well as specific biochemical characteristics.
Molecular Biology of Rhizomelic Chondrodysplasia Punctata
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 6q23.3 and is composed of 11 exons that encode a 323 amino acid protein. The PEX7 encoded protein is the receptor for proteins containing a type-2 peroxisomal targeting sequence, PTS2.
There are four additional disorders with clinical features of RCDP1 called rhizomelic chondrodysplasia type 2 (RCDP2), type 3 (RCDP3), type 4 (RCDP4), 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 section, the PEX5 protein recognizes proteins with PTS1 sequences. The PEX5 gene is located on chromosome 12p13.31 and is composed of 23 exons that generate 26 alternatively spliced mRNAs that collectively encode seven distinct protein isoforms with two, Pex5pS and Pex5pL (or Pex5S and Pex5L for short and long forms, respectively), being the primary functional proteins in peroxisomes. Absence of the Pex5pL (Pex5L) protein is the cause of RCDP5.
RCDP2, RCDP3, and RCDP4 are referred to as single peroxisomal enzyme disorders.
RCDP2 results from defects in the gene encoding dihydroxyacetone phosphate acyltransferase, DHAPAT. The DHAPAT enzyme is encoded by the GNPAT (glyceronephosphate O-acyltransferase) gene. The GNPAT gene is located on chromosome 1q42.2 and is composed of 17 exons that generate two alternatively spliced mRNAs that encode a 680 amino acid protein (isoform 1) and a 619 amino acid protein (isoform 2) both of which contain a PTS1 motif. DHAPAT is a peroxisomal enzyme carrying out one of two pathways in the synthesis of phosphatidic acid (see the Fatty Acid, Triglyceride, and Phospholipid 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 2q31.2 and is composed of 21 exons that encode a 658 amino acid precursor protein which contains a PTS2 motif. Alkyl-DHAP synthase introduces the ether linkage in plasmalogens.
RCDP4 results from defects in the gene (FAR1) encoding fatty acyl-CoA reductase 1. The FAR1 gene is located on chromosome 11p15.3 and is composed of 12 exons that encode a 515 amino acid protein. Fatty acyl-CoA reductase 1 is a peroxisomal tail-anchored protein. The hydrophobic C-terminus of fatty acyl-CoA reductase 1 binds to Pex19p, a cytosolic receptor harboring a C-terminal CAAX motif. This interaction is responsible for the targeting of fatty acyl-CoA reductase 1 to peroxisomes. Fatty acyl-CoA reductase 1 catalyzes the reduction of saturated and unsaturated C16 or C18 fatty acyl-CoA to fatty alcohols which is essential to the production of ether lipids and plasmalogens whose synthesis requires fatty alcohols. Fatty acyl-CoA reductase 1 is also required for wax monoesters production.
Peroxisome Biogenesis and Function
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, PMP) 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.
Clinical Features of RCDP1
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.