Journal Article

Acyl-CoA: Dihydroxyacetonephosphate Acyltransferase: Cloning of the Human cDNA and Resolution of the Molecular Basis in Rhizomelic Chondrodysplasia Punctata Type 2

Rob Ofman, Ewald H. Hettema, Eveline M. Hogenhout, Ubaldo Caruso, Anton O. Muijsers and Ronald J.A. Wanders

in Human Molecular Genetics

Volume 7, issue 5, pages 847-853
Published in print May 1998 | ISSN: 0964-6906
Published online May 1998 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/7.5.847
Acyl-CoA: Dihydroxyacetonephosphate Acyltransferase: Cloning of the Human cDNA and Resolution of the Molecular Basis in Rhizomelic Chondrodysplasia Punctata Type 2

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Rhizomelic chondrodysplasia punctata (RCDP) is a genetic disorder which is clinically characterized by rhizomelic shortening of the upper extremities, typical dysmorphic facial appearance, congenital contractures and severe growth and mental retardation. Patients with RCDP can be subdivided into three subgroups based on biochemical analyses and complementation studies. The largest subgroup contains patients with mutations in the PEX7 gene encoding the PTS2 receptor. This results in multiple peroxisomal abnormalities which includes a deficiency of acyl-CoA:dihydroxyacetonephosphate acyltransferase (DHAPAT), alkyl-dihydroxyacetonephosphate syn-thase (alkyl-DHAP synthase), peroxisomal 3-ketoacyl-CoA thiolase and phytanoyl-CoA hydroxylase, although there are differences in the extent of the deficiencies observed. Patients in the two other subgroups have been reported to be either deficient in the activity of DHAPAT (RCDP type 2) or alkyl-DHAP synthase (RCDP type 3) while no other abnormalities could be observed. To examine whether the gene encoding DHAPAT is mutated in patients with RCDP type 2, we determined the N-terminal amino acid sequence of the enzyme isolated from human placenta. Using this sequence as a query, we identified a 2040 bp open reading frame (ORF) in the human database of expressed sequence tags. Expression of this ORF in the yeast Saccharomyces cerevisiae showed that we have identified the DHAPAT cDNA. The deduced amino acid sequence revealed no PTS2 consensus sequence. In contrast DHAPAT appears to contain a putative PTS1 at the extreme C-terminus. All RCDP type 2 patients analyzed were found to contain mutations in their DHAPATcDNA. This demonstrates that RCDP type 2 is the result of mutations in DHAPAT.

Journal Article.  3820 words.  Illustrated.

Subjects: Genetics and Genomics

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