ABSTRACT
Recently we identified a P408S, P415L allele of beta-glucuronidase in several Mexican patients with mucopolysaccharidosis type VII (Sly syndrome) and presented evidence that both mutations are required to produce the MPS VII allele (Islam et al., 1996). In an attempt to determine whether either of these mutations exists as a benign polymorphism among Mexicans, we developed a PCR method to screen simultaneously for both mutations and used it to screen a population sample of 187 Mexican individuals in the Guadalajara area, all from the north-western states of Mexico. Neither mutation was present in 374 alleles studied. In addition, we had the opportunity to carry out prenatal diagnosis in a fetus at risk for homozygosity for this MPS VII allele at the 15th week of gestation using enzymatic assays as well as by analysis of genomic DNA isolated from cultured amniotic fluid cells. The fetus was found to be heterozygous for the P408S, P415L allele. The newborn's heterozygosity was confirmed after birth by enzyme assays on plasma and leukocytes, and by analysis of DNA from leukocytes.
Subject(s)
Alleles , Glucuronidase/genetics , Mucopolysaccharidosis VII/genetics , Mutation , Prenatal Diagnosis , Amniotic Fluid/cytology , Cells, Cultured , DNA/analysis , DNA/isolation & purification , Gestational Age , Heterozygote , Mexico , Mucopolysaccharidosis VII/diagnosis , Polymerase Chain ReactionABSTRACT
Carbonic anhydrase (CA) II deficiency is characterized by osteopetrosis, renal tubular acidosis, cerebral calcification, and usually severe mental retardation. We describe an Italian boy with this disease whose mental retardation was relatively mild and whose renal tubular acidosis had only a distal component. A novel mutation of a gt-->tt change of splice donor site at the 5' end of intron 6 was demonstrated. Comparison of this patient with two previous Italian families with different mutations illustrates the clinical and molecular heterogeneity of this disease. The identification of the mutation in this family provided the opportunity for prenatal diagnosis in a subsequent pregnancy.
Subject(s)
Acidosis, Renal Tubular/genetics , Carbonic Anhydrases/deficiency , Intellectual Disability/genetics , Osteopetrosis/genetics , Prenatal Diagnosis , Acidosis, Renal Tubular/diagnosis , Carbonic Anhydrases/genetics , Child, Preschool , Female , Humans , Infant, Newborn , Intellectual Disability/diagnosis , Introns/genetics , Male , Mutation , Osteopetrosis/diagnosis , Polymorphism, Single-Stranded Conformational , PregnancyABSTRACT
Mucopolysaccharidosis type VII (MPS VII, Sly syndrome) is an autosomal recessively inherited lysosomal storage disease caused by a deficiency in beta-glucuronidase. We identified and studied a novel allele containing two C-to-T transitions resulting in P408S and P415L alterations, which is present in homozygous state in one Mexican patient and in heterozygous state in another. None of the previous reports describing mutations in the MPS VII gene include Mexican patients. Expression of either of the mutations individually showed only modest effects on the properties of the enzyme. However, expression of the doubly mutant allele resulted in markedly reduced activity and rapid degradation in an early biosynthetic compartment.
Subject(s)
Glucuronidase/genetics , Mucopolysaccharidosis VII/genetics , Mutation , Animals , Base Sequence , Cell Line , DNA Primers , Female , Humans , Infant, Newborn , Mexico , Molecular Sequence Data , Mucopolysaccharidosis VII/ethnology , Mutagenesis, Site-Directed , Polymerase Chain Reaction , Polymorphism, Single-Stranded ConformationalABSTRACT
Reexamination of serum from a child thought to have died of ethylene glycol poisoning showed that the child had methylmalonic acidemia. The gas chromatographic peak identified as ethylene glycol by a clinical laboratory was actually due to propionic acid. Proof of a metabolic basis for the child's symptoms eventually exonerated his mother of the charge of murder.