Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0917816 (
mental retardation
)
15,867
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The peroxisome-biogenesis disorders (PBDs) are a set of often lethal genetic diseases characterized by
mental retardation
and defective peroxisomal matrix protein import. Mutations in
PEX12
are known to underlie the disease in two patients from complementation group 3 of the PBDs. Here we show that all patients from this group carry mutations on both alleles of
PEX12
. A comparison between
PEX12
genotypes and the clinical and cellular phenotypes of the corresponding PBD patients suggests a relatively straightforward relationship between genotype and phenotype in this group of the PBDs, such that the loss of
PEX12
function leads to more-severe cellular and clinical phenotypes. However, one patient who presented relatively mild clinical and cellular phenotypes was a compound heterozygote for two seemingly severe mutations on each
PEX12
allele.
PEX12
mRNA present in the patient's cells was derived from only one allele, the one that carried a 2-bp deletion early in the
PEX12
coding region, c.26,27Delta. The deduced protein product of this mRNA would contain only the first eight amino acids of the protein, and yet this mutant
PEX12
cDNA displayed significant
PEX12
activity in a functional complementation assay. Surprisingly, the
PEX12
/c.26, 27Delta cDNA directed the synthesis of a 29-kD PEX12 protein in vitro, a result that is consistent with translation initiation at a downstream AUG codon. Transfection studies confirmed the expression of similarly sized
PEX12
proteins from the
PEX12
/c.26,27Delta allele. Thus, it appears that translation initiation at internal AUG codons may modulate disease phenotypes and should be considered whenever unexpectedly mild phenotypes result from severe mutations early in the coding region.
...
PMID:Phenotype-genotype relationships in complementation group 3 of the peroxisome-biogenesis disorders. 979 57
