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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.
- Source :
-
American journal of human genetics [Am J Hum Genet] 2002 Mar; Vol. 70 (3), pp. 612-24. Date of Electronic Publication: 2002 Jan 07. - Publication Year :
- 2002
-
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.
- Subjects :
- Amino Acid Sequence
Animals
COS Cells
Chondrodysplasia Punctata, Rhizomelic classification
Chondrodysplasia Punctata, Rhizomelic enzymology
Chondrodysplasia Punctata, Rhizomelic pathology
Codon genetics
DNA Mutational Analysis
Fibroblasts
Frameshift Mutation genetics
Genes, Recessive genetics
Genes, Reporter genetics
Genetic Complementation Test
Homozygote
Humans
Luciferases genetics
Luciferases metabolism
Molecular Sequence Data
Open Reading Frames genetics
Peroxisomal Targeting Signal 2 Receptor
Phenotype
Protein Folding
Protein Structure, Secondary
Receptors, Cytoplasmic and Nuclear chemistry
Repetitive Sequences, Amino Acid genetics
Sequence Alignment
Structure-Activity Relationship
Alleles
Chondrodysplasia Punctata, Rhizomelic genetics
Mutation genetics
Receptors, Cytoplasmic and Nuclear genetics
Receptors, Cytoplasmic and Nuclear metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0002-9297
- Volume :
- 70
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- American journal of human genetics
- Publication Type :
- Academic Journal
- Accession number :
- 11781871
- Full Text :
- https://doi.org/10.1086/338998