Phenylketonuria - genotypes and phenotypes

Article Abstract:

In the May 2, 1991 issue of The New England Journal of Medicine, researchers present the results of a study on the inherited metabolic disorder phenylketonuria (PKU). In a way, the research represents the end of the first era of human genetic research and the beginning of the next. Phenylketonuria results when a patient lacks sufficient activity of the enzyme phenylalanine hydroxylase. Phenylalanine and metabolites accumulate and cause severe mental retardation. If the diet is restricted in phenylalanine, the build-up of by-products can be reduced and the harsh effects of the disorder can be mitigated somewhat. In the past, much research went into identifying the underlying genetic type, or genotype, which was responsible for the phenotype, or the observable traits of the condition. In the case of PKU, not all patients are equally affected. The Journal article reports the results obtained by researchers who have evaluated the ability of different mutant PKU genes to direct the synthesis of phenylalanine hydroxylase when transferred to laboratory cultures. They were able to correlate the features of the gene with the observed variations in phenotype. From here on in, the PKU story is likely to get more complicated. The understanding of the genetic defect is extensive, but other questions remain. For example, 11 of the 31 known mutations involve a single portion of the PKU gene, yet it is not known what this portion of the gene actually contributes to the enzyme structure. Are there any mutations that, instead of affecting the enzyme's structural gene, result in altering the regulation of the gene? Perhaps the most interesting question is also one of the broader questions. Why is PKU as common as it is? Genes as deleterious as PKU are generally weeded out by evolutionary selection; certainly patients with PKU do not pass them on. Do people with only a single mutant PKU gene have some advantage that helps perpetuate the recessive gene? As interesting as the continuing story of genetic research and phenylketonuria might be, at present there is still no way to apply this knowledge to a completely effective treatment for PKU. (Consumer Summary produced by Reliance Medical Information, Inc.)

Phenylketonuria, Amino acid metabolism, Inborn errors of, Inborn errors of amino acid metabolism, Brain diseases, Metabolic, Metabolic brain diseases

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The genetic basis of dwarfism

Article Abstract:

The identification of the location of the gene that causes the most common type of dwarfism may make it easy to test for the presence or absence of the disorder prenatally. Increased understanding of the role of certain genes in influencing skeletal growth and development may result. Achondroplasia, an inherited disorder, is the most common form of dwarfism, with a frequency of 1 per 15,000 to 1 per 40,000 live births. The location of the achondroplasia gene was identified in early 1994 as being on the short arm of human chromosome 4. The gene encodes fibroblast growth factor receptor 3 (FGFR3). FGFR3 may mutate in the DNA of persons with the achondroplasia gene, but not in the DNA from unaffected persons. A mutational "hot spot" in the FGFR3 gene may explain why the genetic makeup of achondroplasia is very consistent. Prenatal diagnosis may reveal the degree of achondroplasia in the offspring of affected parents.

Dwarfism, Achondroplasia

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