Instituto Valenciano de Microbiología

Masía El Romeral
Ctra. de Bétera a San Antonio Km. 0.3
46117 Bétera (Valencia)
Phone. 96 169 17 02
Fax 96 169 16 37
CIF B-96337217


Rhizomelic chondrodysplasia punctata (rhizomelic chondrodysplasia punctata) - Genes PEX7, GNPAT and AGPS

Rhizomelic chondrodysplasia punctata is a process that affects the normal development of many parts of the body, whose main features include skeletal abnormalities, distinctive facial features, mental retardation and respiratory problems. This disease is characterized by shortening the bones of the arms and thighs (rhizomelia). Affected individuals also have a bone abnormality called chondrodysplasia punctata, which affects the growth of long bones and can be seen on radiographs. People with chondrodysplasia punctata Rhizomelic often develop joint deformities or contractures, leading to stiff and painful joints. In reference to the distinctive facial features include: prominent forehead, hypertelorism, midface hypoplasia, a small nose pointing upwards and prominent cheeks. In addition, almost all people affected with cataracts, which are evident at birth (congenital) or develop in early childhood.

Chondrodysplasia punctata Rhizomelic is associated with considerable delay development and profound intellectual disabilities. Most affected children do not reach some skills such as sitting without support, feed themselves, or speak in sentences. Children affected grow much more slowly than other children their age, and many also have seizures. In addition there are frequent recurrent respiratory infections and respiratory problems that can be potentially fatal. Due to serious health problems, most people with chondrodysplasia punctata Rhizomelic survive only in childhood. Although it is rare for children affected live beyond 10 years, some individuals with milder disease characteristics have survived until early adulthood.

Rhizomelic chondrodysplasia punctata is due to genetic alterations in PEX7, GNPAT and AGPS genes. They described three types of Rhizomelic chondrodysplasia punctata distinguished by their genetic cause. Type 1 (RCDP1), it is the most common type and is due to mutations in the gene PEX7. Type 2 (RCDP2) is due to genetic changes in gene GNPAT. Type 3 (RCDP3) takes place as a result of alterations in gene AGPS. These genes are involved in the formation and functioning of peroxisomes, which are saccular compartments inside cells containing necessary to decompose many different substances enzymes, including fatty acids and some toxic compounds. They are also important for the production of lipids that are used in digestion and in the nervous system.

The PEX7 gene, located on the long arm of chromosome 6 (6q23.3), encoding factor synthesis peroxisomal biogenesis 7, which is part of a group peroxisomal assembly protein (PEX). Inside the cells, PEX proteins are responsible for the incorporation of certain enzymes in peroxisomes. Enzymes in these compartments decompose many different substances, including fatty acids and some toxic compounds. They are also important for the synthesis of lipids, which are used in the nervous system. Factor biogenesis peroxisomal 7 transports various enzymes that are essential for the formation and normal function of peroxisomes. The most important of these enzymes is alkylglycerol phosphate synthase (encoded gene from AGPS). Factor biogenesis peroxisomal 7 also carries fitanoil-CoA hydroxylase enzyme encoded by the gene PHYH. This enzyme helps process a type of fatty acid called phytanic acid, obtained from the diet. Phytanic acid is decomposed into smaller molecules that the body uses for energy.

They have been described over 36 mutations in the gene PEX7. Genetic changes associated with RCDP1 often result in a completely non - functional version of peroxisomal biogenesis factor 7 or the coding inhibit this protein. The most frequent mutation responsible for RCDP1 replaces the amino acid leucine at position 292 of the protein with a premature stop signal in the synthesis of peroxisomal biogenesis factor 7 the (Leu292Ter or L292X). This mutation results in a non - functional version of the protein. Genetic mutations responsible PEX7 RCDP1 prevent the peroxisomal biogenesis factor 7 enzymes the transport critical, particularly alkylglycerol phosphate synthase, peroxisomes. Deficiency alkylglycerol phosphate synthase inhibits synthesis plasmalogens. Problems with the production of these lipid molecules appear to be responsible for the signs and symptoms of RCDP1. However, it is unclear how the absence of Plasmalogens results in skeletal abnormalities, mental retardation and other characteristics of this process.

The GNPAT gene, located on the long arm of chromosome 1 (1q42), encoding the enzyme O-acyltransferase glycerophosphate (GNPAT) or dihydroxyacetone acyltransferase (DHAPAT). This enzyme is also found in the peroxisomes, where it is responsible for the first stage in producing plasmalogens. At least five mutations in the gene have been identified GNPAT as Rhizomelic chondrodysplasia punctata responsible type 2 (RCDP2). These mutations prevent the synthesis of a functional GNPAT enzyme. The deficiency of this enzyme disrupts the function of peroxisomes and greatly reduces the amount of plasmalogen inside cells. It is unclear how these alterations cause the shortening of the long bones, intellectual disability, and other features of RCDP2.

The AGPS gene is located on the long arm of chromosome 2 (2q31.2) and encodes alkylglycerol phosphate synthase enzyme. Within peroxisomes, this enzyme is responsible for a critical step in lipid synthesis plasmalogen. Plasmalogens are abundant in myelin that covers nerve cells, and is thought to help protect cells from oxidative stress. Plasmalogens may also play important roles in interactions between lipids and proteins, the transmission of chemical signals in cells, and the fusion of cell membranes.

We found at least three mutations in the gene AGPS in people with Rhizomelic chondrodysplasia punctata type 3 (RCDP3). These mutations change the amino acid groups alkylglycerol phosphate synthase enzyme, modifying enzyme structure and significantly reducing its activity. Phosphate synthase deficiency functional alkylglycerol disrupts the function of peroxisomes and strongly reduces the amount of plasmalogen inside cells. It is unclear how these alterations cause the shortening of the long bones, or intellectual disability and other characteristics of the RCDP3.

This disease is inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests in IVAMI: in IVAMI perform mutation detection Rhizomelic chondrodysplasia punctata associated with types 1, 2 and 3 by the complete PCR amplification of the exons of PEX7, GNPAT and AGPS, respectively, genes and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).