Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rhizomelic chondrodysplasia punctata (RCDP) is a sublethal autosomal recessive disorder characterized by skeletal dysplasia, microcephaly, mental retardation, congenital cataracts, joint contractures, skin changes, and failure to thrive. Prenatal ultrasound diagnosis has been reported during the second trimester of pregnancy. Prenatal diagnosis is also possible from the first trimester onwards by demonstration of peroxisomal dysfunction in cultured chorionic villous or amniotic fluid cells. In all cases reported hitherto, the prenatal diagnosis was established after the birth of a previous affected child. In contrast to these studies in pregnant multiparous women at risk for RCDP, we report on the first case of prenatal ultrasound diagnosis of RCDP at 19 weeks' gestation in a primigravida. In addition, a complex cardiac malformation associated with hypoplasia of the thymus (DiGeorge anomaly) is described.
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PMID:Prenatal ultrasound diagnosis of rhizomelic chondrodysplasia punctata in a primigravida. 799 19

Rhizomelic chondrodysplasia punctata (RCDP) is an autosomal recessive disease characterized clinically by a disproportionately short stature primarily affecting the proximal parts of the extremities, typical dysmorphic facial appearance, congenital contractures and severe growth and mental retardation. Although some patients have single enzyme deficiencies, the majority of RCDP patients (86%) belong to a single complementation group (CG11, also known as complementation group I, Amsterdam nomenclature). Cells from CG11 show a tetrad of biochemical abnormalities: a deficiency of i) dihydroxyacetonephosphate acyltransferase, ii) alkyldihydroxyacetonephosphate synthase, iii) phytanic acid alpha-oxidation and iv) inability to import peroxisomal thiolase. These deficiencies indicate involvement of a component required for correct targeting of these peroxisomal proteins. Deficiencies in peroxisomal targeting are also found in Saccharomyces cerevisiae pex5 and pex7 mutants, which show differential protein import deficiencies corresponding to two peroxisomal targeting sequences (PTS1 and PTS2). These mutants lack their PTS1 and PTS2 receptors, respectively. Like S. cerevisiae pex cells, RCDP cells from CG11 cannot import a PTS2 reporter protein. Here we report the cloning of PEX7 encoding the human PTS2 receptor, based on its similarity to two yeast orthologues. All RCDP patients from CG11 with detectable PEX7 mRNA were found to contain mutations in PEX7. A mutation resulting in C-terminal truncation of PEX7 cosegregates with the disease and expression of PEX7 in RCDP fibroblasts from CG11 rescues the PTS2 protein import deficiency. These findings prove that mutations in PEX7 cause RCDP, CG11.
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PMID:Rhizomelic chondrodysplasia punctata is a peroxisomal protein targeting disease caused by a non-functional PTS2 receptor. 909 Mar 82

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 synthase (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 DHAPAT cDNA. This demonstrates that RCDP type 2 is the result of mutations in DHAPAT.
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PMID:Acyl-CoA:dihydroxyacetonephosphate acyltransferase: cloning of the human cDNA and resolution of the molecular basis in rhizomelic chondrodysplasia punctata type 2. 953 89

Rhizomelic chondrodysplasia punctata (RCDP) is a lethal autosomal recessive disease corresponding to complementation group 11 (CG11), the second most common of the thirteen CGs of peroxisomal biogenesis disorders (PBDs). RCDP is characterized by proximal limb shortening, severely disturbed endochondrial bone formation, and mental retardation, but there is an absence of the neuronal migration defect found in the other PBDs. Plasmalogen biosynthesis and phytanic acid oxidation are deficient, but very long chain fatty acid (VLCFA) oxidation is normal. At the cellular level, RCDP is unique in that the biogenesis of most peroxisomal proteins is normal, but a specific subset of at least four, and maybe more, peroxisomal matrix proteins fail to be imported from the cytosol. In this review, we discuss recent advances in understanding RCDP, most prominently the cloning of the affected gene, PEX7, and identification of PEX7 mutations in RCDP patients. Human PEX7 was identified by virtue of its sequence similarity to its Saccharomyces cerevisiae ortholog, which had previously been shown to encode Pex7p, an import receptor for type 2 peroxisomal targeting sequences (PTS2). Normal human PEX7 expression rescues the cellular defects in cultured RCDP cells, and cDNA sequence analysis has identified a variety of PEX7 mutations in RCDP patients, including a deletion of 100 nucleotides, probably due to a splice site mutation, and a prevalent nonsense mutation which results in loss of the carboxyterminal 32 amino acids. Identification of RCDP as a PTS2 import disorder explains the observation that several, but not all, peroxisomal matrix proteins are mistargeted in this disease; three of the four proteins deficient in RCDP have now been shown to be PTS2-targeted.
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PMID:Rhizomelic chondrodysplasia punctata, a peroxisomal biogenesis disorder caused by defects in Pex7p, a peroxisomal protein import receptor: a minireview. 1022 89