Dataset Information

Mutational spectrum in the PEX7 gene and functional analysis of mutant alleles in 78 patients with rhizomelic chondrodysplasia punctata type 1.

ABSTRACT: Rhizomelic chondrodysplasia punctata (RCDP) is a genetically heterogeneous, autosomal recessive disorder of peroxisomal metabolism that is clinically characterized by symmetrical shortening of the proximal long bones, cataracts, periarticular calcifications, multiple joint contractures, and psychomotor retardation. Most patients with RCDP have mutations in the PEX7 gene encoding peroxin 7, the cytosolic PTS2-receptor protein required for targeting a subset of enzymes to peroxisomes. These enzymes are deficient in cells of patients with RCDP, because of their mislocalization to the cytoplasm. We report the mutational spectrum in the PEX7 gene of 78 patients (including five pairs of sibs) clinically and biochemically diagnosed with RCDP type I. We found 22 different mutations, including 18 novel ones. Furthermore, we show by functional analysis that disease severity correlates with PEX7 allele activity: expression of eight different alleles from patients with severe RCDP failed to restore the targeting defect in RCDP fibroblasts, whereas two alleles found only in patients with mild disease complemented the targeting defect upon overexpression. Surprisingly, one of the mild alleles comprises a duplication of nucleotides 45-52, which is predicted to lead to a frameshift at codon 17 and an absence of functional peroxin 7. The ability of this allele to complement the targeting defect in RCDP cells suggests that frame restoration occurs, resulting in full-length functional peroxin 7, which leads to amelioration of the predicted severe phenotype. This was confirmed in vitro by expression of the eight-nucleotide duplication-containing sequence fused in different reading frames to the coding sequence of firefly luciferase in COS cells.

SUBMITTER: Motley AM

PROVIDER: S-EPMC384941 | biostudies-literature | 2002 Mar

REPOSITORIES: biostudies-literature

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Mutational spectrum in the PEX7 gene and functional analysis of mutant alleles in 78 patients with rhizomelic chondrodysplasia punctata type 1.

Motley Alison M AM Brites Pedro P Gerez Lisya L Hogenhout Eveline E Haasjes Janet J Benne Rob R Tabak Henk F HF Wanders Ronald J A RJ Waterham Hans R HR

American journal of human genetics 20020107 3

Rhizomelic chondrodysplasia punctata (RCDP) is a genetically heterogeneous, autosomal recessive disorder of peroxisomal metabolism that is clinically characterized by symmetrical shortening of the proximal long bones, cataracts, periarticular calcifications, multiple joint contractures, and psychomotor retardation. Most patients with RCDP have mutations in the PEX7 gene encoding peroxin 7, the cytosolic PTS2-receptor protein required for targeting a subset of enzymes to peroxisomes. These enzyme ...[more]

PMID: 11781871

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Project description:BACKGROUND: To describe the neurologic profiles of Rhizomelic chondrodysplasia punctata (RCDP); a peroxisomal disorder clinically characterized by skeletal abnormalities, congenital cataracts, severe growth and developmental impairments and immobility of joints. Defective plasmalogen biosynthesis is the main biochemical feature. METHODS: Observational study including review of clinical and biochemical abnormalities, genotype, presence of seizures and neurophysiological studies of a cohort of 16 patients with RCDP. RESULTS: Patients with the severe phenotype nearly failed to achieve any motor or cognitive skills, whereas patients with the milder phenotype had profound intellectual disability but were able to walk and had verbal communication skills. Eighty-eight percent of patients developed epileptic seizures. The age of onset paralleled the severity of the clinical and biochemical phenotype. Myoclonic jerks, followed by atypical absences were most frequently observed. All patients with clinical seizures had interictal encephalographic evidence of epilepsy. Visual evoked (VEP) and brain auditory potential (BAEP) studies showed initial normal latency times in 93% of patients. Deterioration of VEP occurred in a minority in both the severe and the milder phenotype. BAEP and somatosensory evoked potentials (SSEP) were more likely to become abnormal in the severe phenotype. Plasmalogens were deficient in all patients. In the milder phenotype levels of plasmalogens were significantly higher in erythrocytes than in the severe phenotype. Phytanic acid levels ranged from normal to severely increased, but had no relation with the neurological phenotype. CONCLUSION: Neurodevelopmental deficits and age-related occurrence of seizures are characteristic of RCDP and are related to the rest-activity in plasmalogen biosynthesis. Evoked potential studies are more likely to become abnormal in the severe phenotype, but are of no predictive value in single cases of RCDP.

Project description:Rhizomelic chondrodysplasia punctata type 1 (RCDP1) is a peroxisome biogenesis disorder caused by defects in PEX7 leading to impairment in plasmalogen (Pls) biosynthesis and phytanic acid (PA) oxidation. Pls deficiency is the main pathogenic factor that determines the severity of RCDP. Severe (classic) RCDP patients have negligible Pls levels, congenital cataracts, skeletal dysplasia, growth and neurodevelopmental deficits, and cerebral hypomyelination and cerebellar atrophy on brain MRI. Individuals with milder or nonclassic RCDP have higher Pls levels, better growth and cognitive outcomes. To better understand the pathophysiology of RCDP disorders, we generated an allelic series of Pex7 mice either homozygous for the hypomorphic allele, compound heterozygous for the hypomorphic and null alleles or homozygous for the null allele. Pex7 transcript and protein were almost undetectable in the hypomorphic model, and negligible in the compound heterozygous and null mice. Pex7 deficient mice showed a graded reduction in Pls and increases in C26:0-LPC and PA in plasma and brain according to genotype. Neuropathological evaluation showed significant loss of cerebellar Purkinje cells over time and a decrease in brain myelin basic protein (MBP) content in Pex7 deficient models, with more severe effects correlating with Pex7 genotype. All Pex7 deficient mice exhibited a hyperactive behavior in the open field environment. Brain neurotransmitters analysis of Pex7 deficient mice showed a significant reduction in levels of dopamine, norepinephrine, serotonin and GABA. Also, a significant correlation was found between brain neurotransmitter levels, the hyperactivity phenotype, Pls level and the severity of Pex7 genotype. In conclusion, our study showed evidence of a genotype-phenotype correlation between the severity of Pex7 deficiency and several clinical and neurobiochemical phenotypes in RCDP1 mouse models. We propose that PA accumulation may underlie the cerebellar atrophy seen in older RCDP1 patients, as even relatively low tissue levels were strongly associated with Purkinje cells loss over time in the murine models. Also, our data demonstrate the interrelation between Pls, brain neurotransmitter deficiencies and the neurobehavioral phenotype, which could be further used as a valuable clinical endpoint for therapeutic interventions. Finally, these models show that incremental increases in Pex7 levels result in dramatic improvements in phenotype.

Dataset Information

Mutational spectrum in the PEX7 gene and functional analysis of mutant alleles in 78 patients with rhizomelic chondrodysplasia punctata type 1.

Publications

Mutational spectrum in the PEX7 gene and functional analysis of mutant alleles in 78 patients with rhizomelic chondrodysplasia punctata type 1.

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